Scholars@Duke
Robert J. Lefkowitz

Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine
Medicine, Cardiology
lefko001@receptor-biol.duke.edu
Duke Box 3821, Durham, NC 27710
467 Clin & Res Labs, Durham, NC 27710

Selected Publications

G Protein-Coupled Receptors: A Century of Research and Discovery.

Journal Article Circ Res · June 21, 2024 GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug ... Full text Link to item Cite

G protein-coupled receptors: from radioligand binding to cellular signaling.

Journal Article J Clin Invest · March 1, 2024 Radioligand binding techniques facilitated the identification and study of G-protein coupled receptors that now represent the largest class of targets for therapeutic drugs. ... Full text Link to item Cite

How carvedilol does not activate β2-adrenoceptors.

Journal Article Nat Commun · November 30, 2023 Full text Link to item Cite

Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin.

Journal Article Proc Natl Acad Sci U S A · October 24, 2023 β-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. β-arrestins link agonist-stimulate ... Full text Link to item Cite

Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models.

Journal Article J Clin Invest · September 15, 2023 Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands ... Full text Link to item Cite

Abstract P2154: A Novel Allosteric Modulator Of The β 1 AR Identified By DNA-encoded Small Molecule Library Screening Demonstrates Unique Pharmacology And Function

Conference Circulation Research · August 4, 2023 While traditional β-blockers (i.e. competitive orthosteric antagonists of β-adrenergic receptors; βARs) are widely used as cardiovascular therapeutics, adverse effects such as fatigue and the nonselective inhibition of multiple recepto ... Full text Cite

Loss of biased signaling at a G protein-coupled receptor in overexpressed systems.

Journal Article PLoS One · 2023 G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (Ang ... Full text Link to item Cite

Marc G. Caron (1946-2022).

Journal Article Nat Neurosci · September 2022 Full text Link to item Cite

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.

Journal Article Cell · May 12, 2022 β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in ... Full text Link to item Cite

Loss of Biased Signaling Specificity of the Angiotensin II Type 1 Receptor in Overexpressed Systems.

Journal Article FASEB J · May 2022 G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1 Ile4 Ile8 ]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II ( ... Full text Link to item Cite

Translating science to medicine: The case for physician-scientists.

Journal Article Sci Transl Med · February 16, 2022 As the number of physician-scientists continues to decline, action must be taken to support them as they embark on their careers. ... Full text Link to item Cite

β-Arrestin-Biased Allosteric Modulator Potentiates Carvedilol-Stimulated β Adrenergic Receptor Cardioprotection.

Journal Article Mol Pharmacol · December 2021 β 1 adrenergic receptors (β 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, β 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate ad ... Full text Link to item Cite

The GPCR-β-arrestin complex allosterically activates C-Raf by binding its amino terminus.

Journal Article J Biol Chem · December 2021 G protein-coupled receptors (GPCRs) convert external stimuli into cellular signals through heterotrimeric guanine nucleotide-binding proteins (G-proteins) and β-arrestins (βarrs). In a βarr-dependent signaling pathway, βarrs link GPCRs to various downstrea ... Full text Link to item Cite

Unique Positive Cooperativity Between the β-Arrestin-Biased β-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the β2-Adrenergic Receptor.

Journal Article Mol Pharmacol · November 2021 Among β-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other β-blockers in its ability to elicit β-arrestin-biased agonism, which has been su ... Full text Link to item Cite

Signaling at the endosome: cryo-EM structure of a GPCR-G protein-beta-arrestin megacomplex.

Journal Article FEBS J · April 2021 G protein-coupled receptors (GPCRs) are a large class of cell-surface receptor involved in cellular signaling that are currently the target of over one third of all clinically approved therapeutics. Classically, an agonist-bound, active GPCR couples to and ... Full text Link to item Cite

Allosteric activation of proto-oncogene kinase Src by GPCR-beta-arrestin complexes.

Journal Article J Biol Chem · December 4, 2020 G protein-coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs ... Full text Link to item Cite

Allosteric activation of proto-oncogene kinase Src by GPCR-beta-arrestin complexes.

Journal Article J Biol Chem · December 4, 2020 G protein-coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs ... Full text Link to item Cite

SnapShot: β-Arrestin Functions.

Journal Article Cell · September 3, 2020 The arrestins are ubiquitously expressed adaptor proteins that orchestrate transmembrane signaling cascades triggered by the 7-transmembrane G protein-coupled receptors. While originally discovered as proteins that block receptor-G protein coupling, arrest ... Full text Link to item Cite

Conformational Basis of G Protein-Coupled Receptor Signaling Versatility.

Journal Article Trends Cell Biol · September 2020 G protein-coupled receptors (GPCRs) are privileged structural scaffolds in biology that have the versatility to regulate diverse physiological processes. Interestingly, many GPCR ligands exhibit significant 'bias' - the ability to preferentially activate s ... Full text Link to item Cite

Synthetic nanobodies as angiotensin receptor blockers.

Journal Article Proc Natl Acad Sci U S A · August 18, 2020 There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine ... Full text Link to item Cite

Abstract MP133: Development of β-arrestin-biased Positive Allosteric Modulators for the β 1 Adrenergic Receptor

Conference Circulation Research · July 31, 2020 The β 1 adrenergic receptor (β 1 AR) is a central regulator of cardiac function and an important therapeutic target for cardiac diseases. Two eme ... Full text Cite

The β-arrestin-biased β-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility.

Journal Article Proc Natl Acad Sci U S A · June 2, 2020 A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and incr ... Full text Open Access Link to item Cite

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

Journal Article Nature · March 2020 After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways tha ... Full text Link to item Cite

Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.

Journal Article Science · February 21, 2020 Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear ... Full text Link to item Cite

Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR.

Journal Article Science · February 21, 2020 Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands wit ... Full text Link to item Cite

Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.

Journal Article Nat Struct Mol Biol · December 2019 Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, me ... Full text Link to item Cite

Detergent- and phospholipid-based reconstitution systems have differential effects on constitutive activity of G-protein-coupled receptors.

Journal Article J Biol Chem · September 6, 2019 A hallmark of G-protein-coupled receptors (GPCRs) is the conversion of external stimuli into specific cellular responses. In this tightly-regulated process, extracellular ligand binding by GPCRs promotes specific conformational changes within the seven tra ... Full text Link to item Cite

Mechanism of β2AR regulation by an intracellular positive allosteric modulator.

Journal Article Science · June 28, 2019 Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal stru ... Full text Link to item Cite

Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody.

Journal Article Cell · January 24, 2019 The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody f ... Full text Link to item Cite

Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations.

Journal Article Cell · January 24, 2019 "Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribu ... Full text Link to item Cite

β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility.

Journal Article Skelet Muscle · December 27, 2018 BACKGROUND: β2-adrenergic receptors (β2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of β2AR stimulation on skeletal muscle is anabolic growth, which has l ... Full text Open Access Link to item Cite

Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9.

Journal Article Sci Signal · September 25, 2018 G protein-coupled receptors (GPCRs) use diverse mechanisms to regulate the mitogen-activated protein kinases ERK1/2. β-Arrestins (βArr1/2) are ubiquitous inhibitors of G protein signaling, promoting GPCR desensitization and internalization and serving as s ... Full text Link to item Cite

G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor.

Journal Article Sci Signal · August 21, 2018 Biased agonists of G protein-coupled receptors (GPCRs), which selectively activate either G protein- or β-arrestin-mediated signaling pathways, are of major therapeutic interest because they have the potential to show improved efficacy and specificity as d ... Full text Link to item Cite

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries.

Journal Article Mol Pharmacol · August 2018 Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique al ... Full text Link to item Cite

Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in β-arrestin coupling.

Journal Article Proc Natl Acad Sci U S A · April 10, 2018 The ability of G protein-coupled receptors (GPCRs) to initiate complex cascades of cellular signaling is governed by the sequential coupling of three main transducer proteins, G protein, GPCR kinase (GRK), and β-arrestin. Mounting evidence indicates these ... Full text Link to item Cite

Biased signalling: from simple switches to allosteric microprocessors.

Journal Article Nat Rev Drug Discov · April 2018 G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR ki ... Full text Link to item Cite

A Serendipitous Scientist.

Journal Article Annu Rev Pharmacol Toxicol · January 6, 2018 Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who wer ... Full text Link to item Cite

β-Arrestin2 mediates progression of murine primary myelofibrosis.

Journal Article JCI Insight · December 21, 2017 Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isofor ... Full text Link to item Cite

LB987 New insights into gpcr-transducer coupling

Conference Journal of Investigative Dermatology · October 2017 Full text Cite

Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure.

Journal Article Nature · August 24, 2017 G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ... Full text Link to item Cite

Seven transmembrane receptors

Conference EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS · July 1, 2017 Link to item Cite

β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.

Journal Article Cell Rep · March 21, 2017 Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local pro ... Full text Link to item Cite

Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.

Journal Article Proc Natl Acad Sci U S A · March 7, 2017 β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR-βarr ... Full text Link to item Cite

Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

Journal Article Proc Natl Acad Sci U S A · February 14, 2017 The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor dr ... Full text Link to item Cite

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor.

Journal Article Nat Chem Biol · September 2016 G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies the ability of 'biased agonists' to activate specific subsets of a given receptor's signaling profile. However ... Full text Link to item Cite

GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.

Journal Article Cell · August 11, 2016 Classically, G protein-coupled receptor (GPCR) stimulation promotes G protein signaling at the plasma membrane, followed by rapid β-arrestin-mediated desensitization and receptor internalization into endosomes. However, it has been demonstrated that some G ... Full text Link to item Cite

Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation.

Journal Article Nature · July 21, 2016 G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric pocket propagates conformational change to the receptor cy ... Full text Link to item Cite

Alfred Goodman Gilman (1941-2015).

Journal Article Nature · January 21, 2016 Full text Link to item Cite

The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome.

Journal Article Am J Physiol Heart Circ Physiol · November 2015 Ang II type 1a receptor (AT1aR)-mediated activation of MAPKs contributes to thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). β-Arrestin2 (βarr2) is known to mediate AT1aR-dependent MAPK activation, as well as proproliferative and profib ... Full text Link to item Cite

Inspiring the next generation of physician-scientists.

Journal Article J Clin Invest · August 3, 2015 As academic physician-scientists, one of the most important things we do is mentor young trainee-scientists. There obviously is no one right way to mentor or a set of rules one can follow; it's a very personal matter, and very much depends on one's persona ... Full text Link to item Cite

N-linked glycosylation of protease-activated receptor-1 at extracellular loop 2 regulates G-protein signaling bias.

Journal Article Proc Natl Acad Sci U S A · July 7, 2015 Protease-activated receptor-1 (PAR1) is a G-protein-coupled receptor (GPCR) for the coagulant protease thrombin. Similar to other GPCRs, PAR1 is promiscuous and couples to multiple heterotrimeric G-protein subtypes in the same cell and promotes diverse cel ... Full text Link to item Cite

Introduction

Journal Article The Long Shadow of Vatican II: Living Faith and Negotiating Authority Since the Second Vatican Council · January 1, 2015 Cite

Allosteric modulation of β-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch.

Journal Article J Biol Chem · October 10, 2014 It has recently been appreciated that the angiotensin II type 1 receptor (AT1R), a prototypic member of the G protein-coupled receptor superfamily, also functions as a mechanosensor. Specifically, mechanical stretch activates the AT1R to promote downstream ... Full text Link to item Cite

Visualization of arrestin recruitment by a G-protein-coupled receptor.

Journal Article Nature · August 14, 2014 G-protein-coupled receptors (GPCRs) are critically regulated by β-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the ... Full text Open Access Link to item Cite

Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR).

Journal Article J Biol Chem · May 16, 2014 The concept of "biased agonism" arises from the recognition that the ability of an agonist to induce a receptor-mediated response (i.e. "efficacy") can differ across the multiple signal transduction pathways (e.g. G protein and β-arrestin (βarr)) emanating ... Full text Link to item Cite

Recent developments in biased agonism.

Journal Article Curr Opin Cell Biol · April 2014 The classic paradigm of G protein-coupled receptor (GPCR) activation was based on the understanding that agonist binding to a receptor induces or stabilizes a conformational change to an 'active' conformation. In the past decade, however, it has been appre ... Full text Link to item Cite

Regulation of β2-adrenergic receptor function by conformationally selective single-domain intrabodies.

Journal Article Mol Pharmacol · March 2014 The biologic activity induced by ligand binding to orthosteric or allosteric sites on a G protein-coupled receptor (GPCR) is mediated by stabilization of specific receptor conformations. In the case of the β2 adrenergic receptor, these ligands are generall ... Full text Link to item Cite

Targeting β-arrestin2 Enhances Survival in a Murine Model of Chronic Myeloid Leukemia

Conference Blood · November 15, 2013 AbstractBackgroundChronic myeloid leukemia (CML) is a myeloproliferative neoplasm of hematopoietic stem cells characterized by presenc ... Full text Cite

β-arrestin regulation of myosin light chain phosphorylation promotes AT1aR-mediated cell contraction and migration

Journal Article PLoS ONE · November 8, 2013 Over the last decade, it has been established that G-protein-coupled receptors (GPCRs) signal not only through canonical G-protein-mediated mechanisms, but also through the ubiquitous cellular scaffolds β-arrestin-1 and β-arrestin-2. Previous studies have ... Full text Cite

Discovery of β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor.

Journal Article ACS Med Chem Lett · October 10, 2013 G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on ... Full text Link to item Cite

A brief history of G-protein coupled receptors (Nobel Lecture).

Journal Article Angew Chem Int Ed Engl · June 17, 2013 Full text Link to item Cite

Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.

Journal Article ACS Chem Biol · May 17, 2013 A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inver ... Full text Link to item Cite

Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.

Journal Article Nature · May 2, 2013 The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second ... Full text Link to item Cite

G-protein coupled receptors in virtual screening: Functional fidelity and selectivity

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · April 7, 2013 Link to item Cite

Pharmacological blockade of a β(2)AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model.

Journal Article Cell Cycle · January 15, 2013 Chronic stress is known to have a profound negative impact on human health and has been suggested to influence a number of disease states. However, the mechanisms underlying the deleterious effects of stress remain largely unknown. Stress is known to promo ... Full text Link to item Cite

β-Arrestin regulation of myosin light chain phosphorylation promotes AT1aR-mediated cell contraction and migration.

Journal Article PLoS One · 2013 Over the last decade, it has been established that G-protein-coupled receptors (GPCRs) signal not only through canonical G-protein-mediated mechanisms, but also through the ubiquitous cellular scaffolds β-arrestin-1 and β-arrestin-2. Previous studies have ... Full text Link to item Cite

Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide

Journal Article Nature · 2013 The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second ... Full text Cite

Arrestins come of age: a personal historical perspective.

Journal Article Prog Mol Biol Transl Sci · 2013 Visual arrestin and the two β-arrestins (1 and 2) were originally discovered 25-30 years ago in the context of their ability to desensitize phosphorylated G protein-coupled receptors (rhodopsin and the β2-adrenergic receptor, respectively). A fourth retina ... Full text Link to item Cite

Science Signaling Podcast: 20 November 2012

Journal Article Science Signaling · November 20, 2012 This Podcast features an interview with Robert Lefkowitz, corecipient of this year's Nobel Prize in Chemistry. Lefkowitz has been studying the function of G protein-coupled receptors (GPCRs) for 40 years, and his laboratory has made many important contribu ... Full text Cite

A signal honour

Journal Article Chemistry World · November 1, 2012 Cite

β-Arrestin2 mediates the initiation and progression of myeloid leukemia.

Journal Article Proc Natl Acad Sci U S A · July 31, 2012 β-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although β-arrestins have more recently been implicated as scaffold proteins that interact with various mitogenic and developmental signals, the genetic r ... Full text Link to item Cite

Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling.

Journal Article Mol Syst Biol · June 26, 2012 Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β-arrestins, whose recruitment to the ... Full text Link to item Cite

An interview with Robert J. Lefkowitz.

Journal Article Trends Pharmacol Sci · February 2012 Full text Link to item Cite

Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors.

Journal Article Annu Rev Pharmacol Toxicol · 2012 The concept of biased agonism has recently come to the fore with the realization that seven-transmembrane receptors (7TMRs, also known as G protein-coupled receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations ... Full text Link to item Cite

A tale of two callings.

Journal Article J Clin Invest · October 2011 Full text Open Access Link to item Cite

β-Arrestin-mediated receptor trafficking and signal transduction.

Journal Article Trends Pharmacol Sci · September 2011 β-Arrestins function as endocytic adaptors and mediate trafficking of a variety of cell-surface receptors, including seven-transmembrane receptors (7TMRs). In the case of 7TMRs, β-arrestins carry out these tasks while simultaneously inhibiting upstream G-p ... Full text Link to item Cite

Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling.

Journal Article Trends Biochem Sci · September 2011 β-Arrestins, originally discovered to desensitize activated seven transmembrane receptors (7TMRs; also known as G-protein-coupled receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signal ... Full text Link to item Cite

Quantifying ligand bias at seven-transmembrane receptors.

Journal Article Mol Pharmacol · September 2011 Seven transmembrane receptors (7TMRs), commonly referred to as G protein-coupled receptors, form a large part of the "druggable" genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different fam ... Full text Link to item Cite

Multiple ligand-specific conformations of the β2-adrenergic receptor.

Journal Article Nat Chem Biol · August 21, 2011 Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adap ... Full text Link to item Cite

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.

Journal Article Nature · August 21, 2011 The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is gene ... Full text Link to item Cite

Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.

Journal Article Sci Signal · August 9, 2011 Phosphorylation of G protein-coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arr ... Full text Link to item Cite

β-arrestin deficiency protects against pulmonary fibrosis in mice and prevents fibroblast invasion of extracellular matrix.

Journal Article Sci Transl Med · March 16, 2011 Idiopathic pulmonary fibrosis is a progressive disease that causes unremitting extracellular matrix deposition with resulting distortion of pulmonary architecture and impaired gas exchange. β-Arrestins regulate G protein (heterotrimeric guanine nucleotide- ... Full text Link to item Cite

Therapeutic potential of β-arrestin- and G protein-biased agonists.

Journal Article Trends Mol Med · March 2011 Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disea ... Full text Link to item Cite

International Workshop at the Nobel Forum, Karolinska Institutet on G protein-coupled receptors: finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached?

Journal Article J Recept Signal Transduct Res · October 2010 A meeting was held May 19, 2010 at the Karolinski Institute on Nomenclature in Pharmacology. This meeting occurred in conjunction with the Symposium The Changing World of G Protein Coupled Receptors: From Monomers to Dimers and Receptor Mosaics (Higher-ord ... Full text Link to item Cite

Arresting a transient receptor potential (TRP) channel: beta-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4.

Journal Article J Biol Chem · September 24, 2010 β-Arrestins, originally discovered to desensitize activated G protein-coupled receptors, (aka seven-transmembrane receptors, 7TMRs) also mediate 7TMR internalization and G protein-independent signaling via these receptors. More recently, several regulatory ... Full text Link to item Cite

Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR).

Journal Article Proc Natl Acad Sci U S A · August 24, 2010 beta-Arrestin-mediated signaling downstream of seven transmembrane receptors (7TMRs) is a relatively new paradigm for signaling by these receptors. We examined changes in protein phosphorylation occurring when HEK293 cells expressing the angiotensin II typ ... Full text Link to item Cite

Teaching old receptors new tricks: biasing seven-transmembrane receptors.

Journal Article Nat Rev Drug Discov · May 2010 Seven-transmembrane receptors (7TMRs; also known as G protein-coupled receptors) are the largest class of receptors in the human genome and are common targets for therapeutics. Originally identified as mediators of 7TMR desensitization, beta-arrestins (arr ... Full text Link to item Cite

Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7.

Journal Article Proc Natl Acad Sci U S A · January 12, 2010 Ubiquitously expressed seven-transmembrane receptors (7TMRs) classically signal through heterotrimeric G proteins and are commonly referred to as G protein-coupled receptors. It is now recognized that 7TMRs also signal through beta-arrestins, which act as ... Full text Link to item Cite

G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway.

Journal Article J Biol Chem · December 11, 2009 Wnt ligands conduct their functions in canonical Wnt signaling by binding to two receptors, the single transmembrane low density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) and seven transmembrane (7TM) Frizzled receptors. Subsequently, phosphor ... Full text Link to item Cite

Science Translational Medicine podcast: 7 October 2009

Journal Article Science Translational Medicine · October 7, 2009 A conversation about translational medicine and a Research Article published in the 7 October 2009 issue of Science Translational Medicine. Copyright © 2009, American Association for the Advancement of Science. ... Full text Cite

A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.

Journal Article Sci Transl Med · October 7, 2009 About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric ... Full text Link to item Cite

Arrestin development: emerging roles for beta-arrestins in developmental signaling pathways.

Journal Article Dev Cell · October 2009 Arrestins were identified as mediators of G protein-coupled receptor (GPCR) desensitization and endocytosis. However, it is now clear that they scaffold many intracellular signaling networks to modulate the strength and duration of signaling by diverse typ ... Full text Link to item Cite

Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL.

Journal Article Sci Signal · July 7, 2009 Agonist-induced ubiquitylation and degradation of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play an essential role in surface receptor homeostasis, thereby tuning many physiological processes. Although beta-arr ... Full text Link to item Cite

Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands.

Journal Article Proc Natl Acad Sci U S A · June 16, 2009 CCL19 and CCL21 are endogenous agonists for the seven-transmembrane receptor CCR7. They are equally active in promoting G protein stimulation and chemotaxis. Yet, we find that they result in striking differences in activation of the G protein-coupled recep ... Full text Link to item Cite

Independent beta-arrestin2 and Gq/protein kinase Czeta pathways for ERK stimulated by angiotensin type 1A receptors in vascular smooth muscle cells converge on transactivation of the epidermal growth factor receptor.

Journal Article J Biol Chem · May 1, 2009 Recent studies in receptor-transfected cell lines have demonstrated that extracellular signal-regulated kinase (ERK) activation by angiotensin type 1A receptor and other G protein-coupled receptors can be mediated by both G protein-dependent and beta-arres ... Full text Link to item Cite

beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.

Journal Article J Clin Invest · May 2009 Nicotinic acid is one of the most effective agents for both lowering triglycerides and raising HDL. However, the side effect of cutaneous flushing severely limits patient compliance. As nicotinic acid stimulates the GPCR GPR109A and Gi/Go proteins, here we ... Full text Open Access Link to item Cite

Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.

Journal Article Proc Natl Acad Sci U S A · April 21, 2009 Beta-arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Md ... Full text Link to item Cite

Beta-arrestin1 mediates nicotinic acid induced flushing, but not its antilipolytic effect

Journal Article JOURNAL OF INVESTIGATIVE DERMATOLOGY · April 1, 2009 Link to item Cite

{beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation.

Journal Article J Biol Chem · March 27, 2009 beta-Arrestins, originally discovered as terminators of G protein-coupled receptor signaling, have more recently been appreciated to also function as signal transducers in their own right, although the consequences for cellular physiology have not been wel ... Full text Link to item Cite

Granulocyte chemotaxis and disease expression are differentially regulated by GRK subtype in an acute inflammatory arthritis model (K/BxN).

Journal Article Clin Immunol · October 2008 OBJECTIVE: Chemokine receptors are G-protein coupled receptors (GPCRs) phosphorylated by G-protein receptor kinases (GRKs) after ligand-mediated activation. We hypothesized that GRK subtypes differentially regulate granulocyte chemotaxis and clinical disea ... Full text Link to item Cite

Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor.

Journal Article Mol Pharmacol · September 2008 Trace amines are neurotransmitters whose role in regulating invertebrate physiology has been appreciated for many decades. Recent studies indicate that trace amines may also play a role in mammalian physiology by binding to a novel family of G protein-coup ... Full text Link to item Cite

S-nitrosylation of beta-arrestin regulates beta-adrenergic receptor trafficking.

Journal Article Mol Cell · August 8, 2008 Signal transduction through G protein-coupled receptors (GPCRs) is regulated by receptor desensitization and internalization that follow agonist stimulation. Nitric oxide (NO) can influence these processes, but the cellular source of NO bioactivity and the ... Full text Link to item Cite

Beta-arrestin scaffolding of phosphatidylinositol 4-phosphate 5-kinase Ialpha promotes agonist-stimulated sequestration of the beta2-adrenergic receptor.

Journal Article J Biol Chem · July 25, 2008 Members of the seven-transmembrane receptor (7TMR) superfamily are sequestered from the plasma membrane following stimulation both to limit cellular responses as well as to initiate novel G protein-independent signaling pathways. The best studied mechanism ... Full text Link to item Cite

Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors.

Journal Article Proc Natl Acad Sci U S A · July 22, 2008 Beta-arrestins critically regulate G protein-coupled receptors (GPCRs), also known as seven-transmembrane receptors (7TMRs), both by inhibiting classical G protein signaling and by initiating distinct beta-arrestin-mediated signaling. The recent discovery ... Full text Link to item Cite

Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.

Journal Article Circ Res · July 3, 2008 Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesiz ... Full text Open Access Link to item Cite

Beta-arrestin-mediated localization of smoothened to the primary cilium.

Journal Article Science · June 27, 2008 beta-Arrestins have important roles in the regulation of seven-transmembrane receptors (7TMRs). Smoothened (Smo) is a 7TMR that mediates effects of Hedgehog on developmental processes and whose dysregulation may cause tumorigenesis. beta-Arrestins are requ ... Full text Link to item Cite

Crystallizing thinking about the beta2-adrenergic receptor.

Journal Article Mol Pharmacol · May 2008 Two recently determined crystal structures of the human beta2-adrenergic receptor (beta2AR) provide a long-awaited advance in the field of G protein-coupled receptor research. The beta2AR is only the second member of this, the largest family of receptors e ... Full text Link to item Cite

Beta-arrestin-mediated signaling regulates protein synthesis.

Journal Article J Biol Chem · April 18, 2008 Seven transmembrane receptors (7TMRs) exert strong regulatory influences on virtually all physiological processes. Although it is historically assumed that heterotrimeric G proteins mediate these actions, there is a newer appreciation that beta-arrestins, ... Full text Link to item Cite

The annual ASCI meeting: does nostalgia have a future?

Journal Article J Clin Invest · April 2008 For many academic physician-scientists, the yearly Tri-Societies meeting of the ASCI, AAP, and AFCR during the 1960s, '70s, and '80s was an annual rite of spring and the focal point of the academic year. In this brief essay, I set down some miscellaneous r ... Full text Open Access Link to item Cite

beta-arrestin-biased agonism at the beta2-adrenergic receptor.

Journal Article J Biol Chem · February 29, 2008 Classically, the beta 2-adrenergic receptor (beta 2AR) and other members of the seven-transmembrane receptor (7TMR) superfamily activate G protein-dependent signaling pathways in response to ligand stimulus. It has recently been discovered, however, that a ... Full text Link to item Cite

beta2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics.

Journal Article J Biol Chem · February 1, 2008 G protein-coupled receptor signaling is dynamically regulated by multiple feedback mechanisms, which rapidly attenuate signals elicited by ligand stimulation, causing desensitization. The individual contributions of these mechanisms, however, are poorly un ... Full text Link to item Cite

A beta-arrestin 2 signaling complex mediates lithium action on behavior.

Journal Article Cell · January 11, 2008 Besides their role in desensitization, beta-arrestin 1 and 2 promote the formation of signaling complexes allowing G protein-coupled receptors (GPCR) to signal independently from G proteins. Here we show that lithium, a pharmacological agent used for the m ... Full text Link to item Cite

A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling.

Journal Article Proc Natl Acad Sci U S A · October 16, 2007 For many years, beta-adrenergic receptor antagonists (beta-blockers or betaAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, beta-adrenergic receptor antago ... Full text Link to item Cite

Ubiquitination of beta-arrestin links seven-transmembrane receptor endocytosis and ERK activation.

Journal Article J Biol Chem · October 5, 2007 Beta-arrestin2 and its ubiquitination play crucial roles in both internalization and signaling of seven-transmembrane receptors (7TMRs). To understand the connection between ubiquitination and the endocytic and signaling functions of beta-arrestin, we gene ... Full text Link to item Cite

Targeting hedgehog signaling in medulloblastoma

Conference NEURO-ONCOLOGY · October 1, 2007 Link to item Cite

Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.

Journal Article J Clin Invest · September 2007 Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors (betaARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new s ... Full text Open Access Link to item Cite

Beta-arrestin-biased ligands at seven-transmembrane receptors.

Journal Article Trends Pharmacol Sci · August 2007 Seven-transmembrane receptors (7TMRs), the most common molecular targets of modern drug therapy, are critically regulated by beta-arrestins, which both inhibit classic G-protein signaling and initiate distinct beta-arrestin signaling. The interplay of G-pr ... Full text Link to item Cite

The active conformation of beta-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of beta-arrestins1 and -2.

Journal Article J Biol Chem · July 20, 2007 beta-Arrestins are multifunctional adaptor proteins that regulate seven transmembrane-spanning receptor (7TMR) desensitization and internalization and also initiate alternative signaling pathways. Studies have shown that beta-arrestins undergo a conformati ... Full text Link to item Cite

Functional specialization of beta-arrestin interactions revealed by proteomic analysis.

Journal Article Proc Natl Acad Sci U S A · July 17, 2007 Beta-arrestins are cytosolic proteins that form complexes with seven-transmembrane receptors after agonist stimulation and phosphorylation by the G protein-coupled receptor kinases. They play an essential role in receptor desensitization and endocytosis, a ... Full text Link to item Cite

Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.

Journal Article Cell · May 4, 2007 beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric ... Full text Link to item Cite

Seven transmembrane receptors: something old, something new.

Journal Article Acta Physiol (Oxf) · May 2007 Receptors for hormones, neurotransmitters, drugs, sensory stimuli and many other agents represent the gateway to cellular metabolism and activity. They regulate virtually all physiological processes in mammals. Yet as recently as 40 years ago their very ex ... Full text Link to item Cite

Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression.

Journal Article J Biol Chem · April 13, 2007 Beta-arrestin1, which regulates many aspects of seven transmembrane receptor (7TMR) biology, has also been shown to serve as an adaptor, which brings Mdm2, an E3 ubiquitin ligase to the insulin-like growth factor-1 receptor (IGF-1R), leading to its proteas ... Full text Link to item Cite

Seven transmembrane receptors: a brief personal retrospective.

Journal Article Biochim Biophys Acta · April 2007 Receptors have fascinated biologists for more than a century and they have fascinated me for the entirety of my own research career. The seven transmembrane receptors, also known as G protein coupled receptors, represent the largest of the several families ... Full text Link to item Cite

Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins.

Journal Article Science · February 2, 2007 Seven-transmembrane receptor (7TMR) signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide-binding protein Gq and is terminated by receptor desensitization and degradation of ... Full text Link to item Cite

Beta-arrestins and cell signaling.

Journal Article Annu Rev Physiol · 2007 Upon their discovery, beta-arrestins 1 and 2 were named for their capacity to sterically hinder the G protein coupling of agonist-activated seven-transmembrane receptors, ultimately resulting in receptor desensitization. Surprisingly, recent evidence shows ... Full text Link to item Cite

Introduction to special section on β-arrestins

Journal Article Annual Review of Physiology · January 1, 2007 Full text Cite

New roles for beta-arrestins in cell signaling: not just for seven-transmembrane receptors.

Journal Article Mol Cell · December 8, 2006 beta-arrestins, originally discovered as molecules that bind to and desensitize the activated and phosphorylated form of the G protein-coupled beta2-adrenergic receptor (beta2-AR), have recently emerged as multifunctional adaptor/scaffold proteins that dyn ... Full text Link to item Cite

G protein-coupled receptor kinase and beta-arrestin-mediated desensitization of the angiotensin II type 1A receptor elucidated by diacylglycerol dynamics.

Journal Article J Biol Chem · November 24, 2006 Receptor desensitization progressively limits responsiveness of cells to chronically applied stimuli. Desensitization in the continuous presence of agonist has been difficult to study with available assay methods. Here, we used a fluorescence resonance ene ... Full text Link to item Cite

Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.

Journal Article Proc Natl Acad Sci U S A · October 31, 2006 The G protein-coupled receptor kinases (GRKs) and beta-arrestins, families of molecules essential to the desensitization of G protein-dependent signaling via seven-transmembrane receptors (7TMRs), have been recently shown to also transduce G protein-indepe ... Full text Link to item Cite

Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.

Journal Article Mol Cell Biol · October 2006 Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of ... Full text Open Access Link to item Cite

Trafficking of G protein-coupled receptors.

Journal Article Circ Res · September 15, 2006 G protein-coupled receptors (GPCRs) play an integral role in the signal transduction of an enormous array of biological phenomena, thereby serving to modulate at a molecular level almost all components of human biology. This role is nowhere more evident th ... Full text Open Access Link to item Cite

G-protein-coupled receptor kinase specificity for beta-arrestin recruitment to the beta2-adrenergic receptor revealed by fluorescence resonance energy transfer.

Journal Article J Biol Chem · July 21, 2006 The small family of G-protein-coupled receptor kinases (GRKs) regulate cell signaling by phosphorylating heptahelical receptors, thereby promoting receptor interaction with beta-arrestins. This switches a receptor from G-protein activation to G-protein des ... Full text Link to item Cite

Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation.

Journal Article J Biol Chem · April 21, 2006 Parathyroid hormone (PTH) regulates calcium homeostasis via the type I PTH/PTH-related peptide (PTH/PTHrP) receptor (PTH1R). The purpose of the present study was to identify the contributions of distinct signaling mechanisms to PTH-stimulated activation of ... Full text Link to item Cite

beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.

Journal Article J Biol Chem · January 13, 2006 Physiological effects of beta adrenergic receptor (beta2AR) stimulation have been classically shown to result from G(s)-dependent adenylyl cyclase activation. Here we demonstrate a novel signaling mechanism wherein beta-arrestins mediate beta2AR signaling ... Full text Link to item Cite

GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling.

Journal Article Trends Endocrinol Metab · 2006 Stimulation of cell-surface seven-transmembrane receptors (7TMRs) elicits biological responses to a wide range of extracellular signals, including many hormones. Classically, heterotrimeric GTP-binding proteins (G proteins) are recruited to the activated c ... Full text Link to item Cite

Angiotensin II-stimulated signaling through G proteins and beta-arrestin.

Journal Article Sci STKE · November 22, 2005 Beta-arrestin, originally identified as a protein that inhibits heterotrimeric guanine nucleotide-binding protein (G protein) coupling to cognate seven-transmembrane receptors [(7TMRs), also known as G protein-coupled receptors (GPCRs)], is currently being ... Full text Link to item Cite

When 7 transmembrane receptors are not G protein-coupled receptors.

Journal Article J Clin Invest · November 2005 Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal via G protein-independent mechanisms. However, the physiol ... Full text Open Access Link to item Cite

Seven-transmembrane receptor signaling through beta-arrestin.

Journal Article Sci STKE · November 1, 2005 Cell surface receptors are important communicators of external stimuli to the cell interior where they lead to initiation of various signaling pathways and cellular responses. The largest receptor family is the seven-transmembrane receptor (7TMR) family, w ... Full text Link to item Cite

An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.

Journal Article Cell · July 29, 2005 Dopamine plays an important role in the etiology of schizophrenia, and D2 class dopamine receptors are the best-established target of antipsychotic drugs. Here we show that D2 class-receptor-mediated Akt regulation involves the formation of signaling compl ... Full text Link to item Cite

{beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase.

Journal Article J Biol Chem · July 1, 2005 The insulin-like growth factor-1 receptor (IGF-1R) plays important roles in physiological growth and aging as well as promoting several crucial functions in cancer cells. However, the molecular mechanisms involved in expression and down-regulation of IGF-1 ... Full text Link to item Cite

The sustainability of interactions between the orexin-1 receptor and beta-arrestin-2 is defined by a single C-terminal cluster of hydroxy amino acids and modulates the kinetics of ERK MAPK regulation.

Journal Article Biochem J · May 1, 2005 The orexin-1 receptor interacts with beta-arrestin-2 in an agonist-dependent manner. In HEK-293T cells, these two proteins became co-internalized into acidic endosomes. Truncations from the C-terminal tail did not prevent agonist-induced internalization of ... Full text Link to item Cite

Transduction of receptor signals by beta-arrestins.

Journal Article Science · April 22, 2005 The transmission of extracellular signals to the interior of the cell is a function of plasma membrane receptors, of which the seven transmembrane receptor family is by far the largest and most versatile. Classically, these receptors stimulate heterotrimer ... Full text Link to item Cite

Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes.

Journal Article J Biol Chem · April 15, 2005 Angiotensin II type 1a (AT1a), vasopressin V2, and neurokinin 1 (NK1) receptors are seven-transmembrane receptors (7TMRs) that bind and co-internalize with the multifunctional adaptor protein, beta-arrestin. These receptors also lead to robust and persiste ... Full text Link to item Cite

Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis.

Journal Article Mol Pharmacol · April 2005 Chemotaxis is a cellular response that directs cell migration toward a chemical gradient and is fundamental to a variety of cellular processes. The receptors for most known chemokines belong to the seven transmembrane-spanning superfamily and signal throug ... Full text Link to item Cite

beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation.

Journal Article J Biol Chem · March 4, 2005 beta-Arrestins were initially shown, in conjunction with G protein-coupled receptor kinases, to be involved in the desensitization and internalization of activated seven-transmembrane receptors. Recently, beta-arrestin 2 has been shown to act as a signal m ... Full text Link to item Cite

Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

Journal Article Circulation · February 8, 2005 BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the ... Full text Open Access Link to item Cite

Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor.

Journal Article Proc Natl Acad Sci U S A · February 1, 2005 Signaling through beta-arrestins is a recently appreciated mechanism used by seven-transmembrane receptors. Because G protein-coupled receptor kinase (GRK) phosphorylation of such receptors is generally a prerequisite for beta-arrestin binding, we studied ... Full text Link to item Cite

Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling.

Journal Article Proc Natl Acad Sci U S A · February 1, 2005 beta-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor endocytosis, and some aspects of receptor signaling. We have us ... Full text Link to item Cite

Summary of Wenner-Gren international symposium receptor-receptor interactions among heptaspanning membrane receptors: from structure to function.

Journal Article J Mol Neurosci · 2005 Listening to the talks delivered at the symposium during this 2 1/2-d meeting left me with the feeling that this was a field that has truly come of age in the past few years. Although the earliest observations, a number of them by the organizers of the mee ... Full text Link to item Cite

Activation dependent conformational changes in beta-arrestin 2

Conference BIOPHYSICAL JOURNAL · January 1, 2005 Link to item Cite

Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2.

Journal Article J Biol Chem · December 31, 2004 Protease-activated receptor-2 (PAR-2) is activated by trypsin-like serine proteases and can promote cell migration through an ERK1/2-dependent pathway, involving formation of a scaffolding complex at the leading edge of the cell. Previous studies also show ... Full text Link to item Cite

Activation-dependent conformational changes in {beta}-arrestin 2.

Journal Article J Biol Chem · December 31, 2004 Beta-arrestins are multifunctional adaptor proteins, which mediate desensitization, endocytosis, and alternate signaling pathways of seven membrane-spanning receptors (7MSRs). Crystal structures of the basal inactive state of visual arrestin (arrestin 1) a ... Full text Link to item Cite

Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2.

Journal Article Science · December 24, 2004 Binding of Sonic Hedgehog (Shh) to Patched (Ptc) relieves the latter's tonic inhibition of Smoothened (Smo), a receptor that spans the cell membrane seven times. This initiates signaling which, by unknown mechanisms, regulates vertebrate developmental proc ... Full text Link to item Cite

Resonating to the music of ubiquitination.

Journal Article Nat Methods · December 2004 Full text Link to item Cite

PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs/Gi switching.

Journal Article Cell Signal · December 2004 Recently, it has been shown that PKA-mediated phosphorylation of the beta(2)-adrenergic receptor (beta(2)-AR) by the cyclic AMP-dependent protein kinase (PKA) reduces its affinity for G(s) and increases its affinity for G(i). Here we demonstrate that, like ... Full text Link to item Cite

Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2.

Journal Article J Biol Chem · November 12, 2004 Binding of beta-arrestins to seven-membrane-spanning receptors (7MSRs) not only leads to receptor desensitization and endocytosis but also elicits additional signaling processes. We recently proposed that stimulation of the angiotensin type 1A (AT(1A)) rec ... Full text Link to item Cite

beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1.

Journal Article Mol Cell Biol · October 2004 beta-arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR ... Full text Open Access Link to item Cite

Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor.

Journal Article J Biol Chem · August 20, 2004 The seven-membrane-spanning angiotensin II type 1A receptor activates the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) by distinct pathways dependent on either G protein (likely G(q)/G(11)) or beta-arrestin2. He ... Full text Link to item Cite

The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels.

Journal Article Proc Natl Acad Sci U S A · August 10, 2004 Epithelial Na(+) channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, with loss of this inhibition le ... Full text Open Access Link to item Cite

Historical review: a brief history and personal retrospective of seven-transmembrane receptors.

Journal Article Trends Pharmacol Sci · August 2004 Pharmacologists have studied receptors for more than a century but a molecular understanding of their properties has emerged only during the past 30-35 years. In this article, I provide a personal retrospective of how developments and discoveries primarily ... Full text Link to item Cite

Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery.

Journal Article Mol Pharmacol · July 2004 G protein-coupled receptor regulation by G protein-coupled receptor kinases and beta-arrestins can lead to desensitization and subsequent internalization of the receptor. In in vitro and cellular systems, beta-arrestins do not seem to play a major role in ... Full text Link to item Cite

Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors.

Journal Article Science · June 25, 2004 Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) asso ... Full text Link to item Cite

beta-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6.

Journal Article J Biol Chem · June 11, 2004 Seven transmembrane receptors mediate diverse physiological responses including hormone action, olfaction, neurotransmission, and chemotaxis. Human D6 is a non-signaling seven-transmembrane receptor expressed on lymphatic endothelium interacting with most ... Full text Link to item Cite

beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha.

Journal Article Proc Natl Acad Sci U S A · June 8, 2004 In addition to their roles in desensitization and signaling of seven-membrane-spanning receptors, beta-arrestins have been more recently implicated in regulating non-seven-membrane-spanning receptor pathways. By using a yeast two-hybrid screen, we identifi ... Full text Link to item Cite

G protein-coupled receptor kinase function is essential for chemosensation in C. elegans.

Journal Article Neuron · May 27, 2004 G protein-coupled receptors (GPCRs) mediate diverse signaling processes, including olfaction. G protein-coupled receptor kinases (GRKs) are important regulators of G protein signal transduction that specifically phosphorylate activated GPCRs to terminate s ... Full text Link to item Cite

Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.

Journal Article J Neurosci · May 12, 2004 Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine ... Full text Open Access Link to item Cite

Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation.

Journal Article J Clin Invest · May 2004 Antibodies specific for the beta(1)-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these antibodies actually contribute to the pathogenesis of ... Full text Open Access Link to item Cite

Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation.

Journal Article The Journal of clinical investigation · May 1, 2004 Antibodies specific for the beta(1)-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these antibodies actually contribute to the pathogenesis of ... Cite

beta-arrestins: traffic cops of cell signaling.

Journal Article Curr Opin Cell Biol · April 2004 Once thought to function only in the desensitization of seven membrane spanning receptors (7MSRs), the ubiquitous beta-arrestin molecules are increasingly appreciated to play important roles in the endocytosis and signaling of these receptors. These functi ... Full text Link to item Cite

Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2.

Journal Article J Biol Chem · February 27, 2004 beta-Arrestin2 not only plays essential roles in seven membrane-spanning receptor desensitization and internalization but also functions as a signal transducer in mitogen-activated protein kinase cascades. Here we show that the angiotensin II type 1A recep ... Full text Link to item Cite

G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation.

Journal Article Am J Physiol Lung Cell Mol Physiol · February 2004 G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis ... Full text Link to item Cite

Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance.

Journal Article J Biol Chem · January 16, 2004 Kappa opioid receptor (KOR) desensitization was previously shown to follow agonist-dependent phosphorylation of serine 369 by G-protein receptor kinase (GRK) and beta-arrestin binding in transfected cells. To study the in vivo effects induced by phosphoryl ... Full text Link to item Cite

Desensitization of G protein-coupled receptors and neuronal functions.

Journal Article Annu Rev Neurosci · 2004 G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can ... Full text Link to item Cite

G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal.

Journal Article Br J Pharmacol · January 2004 1. Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor de ... Full text Link to item Cite

beta-arrestins: Master regulators of seven membrane spanning receptors

Conference JOURNAL OF PHARMACOLOGICAL SCIENCES · January 1, 2004 Link to item Cite

Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis.

Journal Article J Biol Chem · December 19, 2003 beta-arrestins (1 and 2) are widely expressed cytosolic proteins that play central roles in G protein-coupled receptor signaling. beta-arrestin1 is also recruited to the insulin-like growth factor 1 (IGF-1) receptor, a receptor tyrosine kinase, upon agonis ... Full text Link to item Cite

Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6.

Journal Article J Immunol · December 1, 2003 Directed migration of polymorphonuclear neutrophils (PMN) is required for adequate host defense against invading organisms and leukotriene B(4) (LTB(4)) is one of the most potent PMN chemoattractants. LTB(4) exerts its action via binding to BLT1, a G prote ... Full text Link to item Cite

Regulation of V2 vasopressin receptor degradation by agonist-promoted ubiquitination.

Journal Article J Biol Chem · November 14, 2003 The seven-transmembrane-spanning vasopressin V2 receptor (V2R) is a Gs-coupled receptor that is rapidly phosphorylated and internalized following stimulation with the agonist, arginine-vasopressin. Herein, we show that the V2R is ubiquitinated following ag ... Full text Link to item Cite

Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice.

Journal Article J Neurosci · November 12, 2003 The reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of mu-opioid receptors (muOR). Both mu-opioid and dopamine receptors are members of the G-protein-coupled receptor (GPCR) family of pro ... Full text Open Access Link to item Cite

Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling.

Journal Article Biochem J · November 1, 2003 Beta-arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated second messenger signalling pathways. The binding of beta-arre ... Full text Link to item Cite

N-formyl peptide receptors internalize but do not recycle in the absence of arrestins.

Journal Article J Biol Chem · October 24, 2003 Arrestins mediate phosphorylation-dependent desensitization, internalization, and initiation of signaling cascades for the majority of G protein-coupled receptors (GPCRs). Many GPCRs undergo agonist-mediated internalization through arrestin-dependent mecha ... Full text Link to item Cite

Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2.

Journal Article Proc Natl Acad Sci U S A · September 16, 2003 Stimulation of a mutant angiotensin type 1A receptor (DRY/AAY) with angiotensin II (Ang II) or of a wild-type receptor with an Ang II analog ([sarcosine1,Ile4,Ile8]Ang II) fails to activate classical heterotrimeric G protein signaling but does lead to recr ... Full text Open Access Link to item Cite

Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways.

Journal Article J Biol Chem · September 12, 2003 Agonist-induced phosphorylation of beta-adrenergic receptors (beta ARs) by G protein-coupled receptor kinases (GRKs) results in their desensitization followed by internalization. Whether protein kinase A (PKA)-mediated phosphorylation of beta ARs, particul ... Full text Link to item Cite

Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling.

Journal Article Science · September 5, 2003 beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, ... Full text Link to item Cite

Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4.

Journal Article Science · September 5, 2003 Wnt proteins, regulators of development in many organisms, bind to seven transmembrane-spanning (7TMS) receptors called frizzleds, thereby recruiting the cytoplasmic molecule dishevelled (Dvl) to the plasma membrane.Frizzled-mediated endocytosis of Wg (a D ... Full text Link to item Cite

Beta-arrestin-2 regulates the development of allergic asthma.

Journal Article J Clin Invest · August 2003 Asthma is a chronic inflammatory disorder of the airways that is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. Migration of Th2 cells to the lung is key to their inflammatory function and is regulated in large part ... Full text Open Access Link to item Cite

GIPC interacts with the beta1-adrenergic receptor and regulates beta1-adrenergic receptor-mediated ERK activation.

Journal Article J Biol Chem · July 11, 2003 Beta1-adrenergic receptors, expressed at high levels in the human heart, have a carboxyl-terminal ESKV motif that can directly interact with PDZ domain-containing proteins. Using the beta1-adrenergic receptor carboxyl terminus as bait, we identified the no ... Full text Link to item Cite

G-protein-coupled receptor (GPCR) kinase phosphorylation and beta-arrestin recruitment regulate the constitutive signaling activity of the human cytomegalovirus US28 GPCR.

Journal Article J Biol Chem · June 13, 2003 Phosphorylation of G-protein-coupled receptors (GPCRs) by GRKs and subsequent recruitment of beta-arrestins to agonist-occupied receptors serves to terminate or attenuate signaling by blocking G-proteins from further interaction with the receptors. Human c ... Full text Link to item Cite

Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gbetagamma.

Journal Article Science · May 23, 2003 The phosphorylation of heptahelical receptors by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor kinases (GRKs) is a universal regulatory mechanism that leads to desensitization of G protein signaling and to the activation of ... Full text Link to item Cite

Purification, crystallization and preliminary X-ray diffraction studies of a complex between G protein-coupled receptor kinase 2 and Gbeta1gamma2.

Journal Article Acta Crystallogr D Biol Crystallogr · May 2003 G protein-coupled receptor kinase 2 (GRK2) phosphorylates activated G protein-coupled receptors (GPCRs), which ultimately leads to their desensitization and/or downregulation. The enzyme is recruited to the plasma membrane via the interaction of its carbox ... Full text Open Access Link to item Cite

Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice.

Journal Article Neuron · April 24, 2003 Brain dopaminergic transmission is a critical component in numerous vital functions, and its dysfunction is involved in several disorders, including addiction and Parkinson's disease. Responses to dopamine are mediated via G protein-coupled dopamine recept ... Full text Link to item Cite

Trafficking patterns of beta-arrestin and G protein-coupled receptors determined by the kinetics of beta-arrestin deubiquitination.

Journal Article J Biol Chem · April 18, 2003 Agonist-dependent internalization of G protein-coupled receptors via clathrin-coated pits is dependent on the adaptor protein beta-arrestin, which interacts with elements of the endocytic machinery such as AP2 and clathrin. For the beta(2)-adrenergic recep ... Full text Link to item Cite

An interview with Professor Robert J. Lefkowitz, M.D. Interview by Vicki Glaser.

Journal Article Assay Drug Dev Technol · April 2003 Robert J. Lefkowitz, M.D., is James B. Duke Professor of Medicine and Professor of Biochemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz received a Bachelor's degree ... Full text Open Access Link to item Cite

The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.

Journal Article J Biol Chem · February 21, 2003 By binding to agonist-activated G protein-coupled receptors (GPCRs), beta-arrestins mediate homologous receptor desensitization and endocytosis via clathrin-coated pits. Recent data suggest that beta-arrestins also contribute to GPCR signaling by acting as ... Full text Link to item Cite

Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference.

Journal Article Proc Natl Acad Sci U S A · February 18, 2003 Beta-arrestins bind to activated G protein-coupled receptor kinase-phosphorylated receptors, which leads to their desensitization with respect to G proteins, internalization via clathrin-coated pits, and signaling via a growing list of "scaffolded" pathway ... Full text Open Access Link to item Cite

beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi.

Journal Article Proc Natl Acad Sci U S A · February 4, 2003 Phosphorylation of the beta(2) adrenoreceptor (beta(2)AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (G(s)) to inhibitory guanine nucleotide regulatory protein (G(i)). b ... Full text Open Access Link to item Cite

Homo- and hetero-oligomerization of thyrotropin-releasing hormone (TRH) receptor subtypes. Differential regulation of beta-arrestins 1 and 2.

Journal Article J Biol Chem · December 27, 2002 G-protein-coupled receptors (GPCRs) are regulated by a complex network of mechanisms such as oligomerization and internalization. Using the GPCR subtypes for thyrotropin-releasing hormone (TRHR1 and TRHR2), the aim of this study was to determine if subtype ... Full text Link to item Cite

Overview of the Alliance for Cellular Signaling.

Journal Article Nature · December 12, 2002 The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells--B lymphocytes (the cells of the immune system) and cardiac myocytes--to fac ... Full text Link to item Cite

Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.

Journal Article J Neurosci · December 1, 2002 Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously tha ... Full text Open Access Link to item Cite

Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins.

Journal Article Science · October 25, 2002 Catecholamines signal through the beta2-adrenergic receptor by promoting production of the second messenger adenosine 3',5'-monophosphate (cAMP). The magnitude of this signal is restricted by desensitization of the receptors through their binding to beta-a ... Full text Link to item Cite

Beta 2-adrenergic receptor stimulated, G protein-coupled receptor kinase 2 mediated, phosphorylation of ribosomal protein P2.

Journal Article Biochemistry · October 22, 2002 G protein-coupled receptor kinases are well characterized for their ability to phosphorylate and desensitize G protein-coupled receptors (GPCRs). In addition to phosphorylating the beta2-adrenergic receptor (beta2AR) and other receptors, G protein-coupled ... Full text Link to item Cite

Regulation of G protein-coupled receptor signaling by scaffold proteins.

Journal Article Circ Res · October 18, 2002 The actions of many hormones and neurotransmitters are mediated through stimulation of G protein-coupled receptors. A primary mechanism by which these receptors exert effects inside the cell is by association with heterotrimeric G proteins, which can activ ... Full text Open Access Link to item Cite

Seven-transmembrane receptors.

Journal Article Nat Rev Mol Cell Biol · September 2002 Seven-transmembrane receptors, which constitute the largest, most ubiquitous and most versatile family of membrane receptors, are also the most common target of therapeutic drugs. Recent findings indicate that the classical models of G-protein coupling and ... Full text Link to item Cite

Phosphorylation of beta-arrestin2 regulates its function in internalization of beta(2)-adrenergic receptors.

Journal Article Biochemistry · August 27, 2002 Beta-arrestins mediate agonist-dependent desensitization and internalization of G protein-coupled receptors. Previously, we have shown that phosphorylation of beta-arrestin1 by ERKs at Ser-412 regulates its association with clathrin and its function in pro ... Full text Link to item Cite

Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system.

Journal Article J Biol Chem · August 23, 2002 While classically viewed as a prototypic G(s) and adenylyl cyclase-coupled G protein-coupled receptor, recent studies have indicated that some aspects of beta(2)-adrenergic receptor (beta(2)-AR) signaling are inhibited by pertussis toxin, indicating that t ... Full text Link to item Cite

Src-dependent tyrosine phosphorylation regulates dynamin self-assembly and ligand-induced endocytosis of the epidermal growth factor receptor.

Journal Article J Biol Chem · July 19, 2002 Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. El ... Full text Link to item Cite

Inhibition of betaARK1 restores impaired biochemical beta-adrenergic receptor responsiveness but does not rescue CREB(A133) induced cardiomyopathy.

Journal Article J Mol Cell Cardiol · June 2002 The myocardial beta-adrenergic receptor (betaAR) system plays a key role in dysfunctional signaling and physiology of the failing heart. Recently we described a murine model of dilated cardiomyopathy (DCM) produced by cardiac-specific expression of a domin ... Full text Link to item Cite

Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice.

Journal Article Proc Natl Acad Sci U S A · May 28, 2002 Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived factor-1 (CXCL12) acting via G protein-coupled receptors. Be ... Full text Open Access Link to item Cite

beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.

Journal Article J Biol Chem · March 15, 2002 beta-Arrestins are cytosolic proteins that mediate homologous desensitization of G protein-coupled receptors (GPCRs) by binding to agonist-occupied receptors and by uncoupling them from heterotrimeric G proteins. The recent finding that beta-arrestins bind ... Full text Link to item Cite

Arresting developments in heptahelical receptor signaling and regulation.

Journal Article Trends Cell Biol · March 2002 It is well established that the function of most heptahelical receptors (seven-transmembrane-span receptors; 7TMRs) is tightly regulated by the desensitizing actions of arrestins. Desensitization is the waning of 7TMR-mediated signals after prolonged expos ... Full text Link to item Cite

Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins.

Journal Article Prog Neurobiol · February 2002 Sequestration of G protein-coupled receptors from the cell surface is a commonly observed phenomenon following agonist-stimulation. This process is now believed to be important for receptor resensitization as well as for signal transduction. Over the years ... Full text Link to item Cite

The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.

Journal Article J Cell Sci · February 1, 2002 beta-Arrestins are versatile adapter proteins that form complexes with most G-protein-coupled receptors (GPCRs) following agonist binding and phosphorylation of receptors by G-protein-coupled receptor kinases (GRKs). They play a central role in the interre ... Full text Open Access Link to item Cite

G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95.

Journal Article J Biol Chem · January 11, 2002 We previously reported that the beta(1)-adrenergic receptor (beta(1)AR) associates with PSD-95 through a PDZ domain-mediated interaction, by which PSD-95 modulates beta(1)AR function and facilitates the physical association of beta(1)AR with other synaptic ... Full text Link to item Cite

beta -Arrestins regulate protease-activated receptor-1 desensitization but not internalization or Down-regulation.

Journal Article J Biol Chem · January 11, 2002 The widely expressed beta-arrestin isoforms 1 and 2 bind phosphorylated G protein-coupled receptors (GPCRs) and mediate desensitization and internalization. Phosphorylation of protease-activated receptor-1 (PAR1), a GPCR for thrombin, is important for dese ... Full text Link to item Cite

Seven-transmembrane-spanning receptors and heart function.

Journal Article Nature · January 10, 2002 Understanding precisely how the heart can recognize and respond to many different extracellular signalling molecules, such as neurotransmitters, hormones and growth factors, will aid the identification of new therapeutic targets through which cardiovascula ... Full text Link to item Cite

beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins.

Journal Article Proc Natl Acad Sci U S A · December 18, 2001 One aspect of the function of the beta-arrestins is to serve as scaffold or adapter molecules coupling G-protein coupled receptors (GPCRs) to signal transduction pathways distinct from traditional second messenger pathways. Here we report the identificatio ... Full text Open Access Link to item Cite

Binding of the beta2 adrenergic receptor to N-ethylmaleimide-sensitive factor regulates receptor recycling.

Journal Article J Biol Chem · November 30, 2001 Following agonist stimulation, most G protein-coupled receptors become desensitized and are internalized, either to be degraded or recycled back to the cell surface. What determines the fate of a specific receptor type after it is internalized is poorly un ... Full text Link to item Cite

beta -Arrestin-mediated recruitment of the Src family kinase Yes mediates endothelin-1-stimulated glucose transport.

Journal Article J Biol Chem · November 23, 2001 The insulin and the endothelin type A (ETA) receptor both can couple into the heterotrimeric G protein alpha(q/11) (Galpha(q/11)), leading to Galpha(q/11) tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and subsequent stimulation of glu ... Full text Link to item Cite

Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

Journal Article Circulation · November 13, 2001 BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotr ... Full text Open Access Link to item Cite

Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin.

Journal Article Science · November 9, 2001 Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, there has been little evidence connecting ubiquitination with regulation of mammalian G protein (heterotrimeric guanine nuc ... Full text Link to item Cite

beta-Arrestin-mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis.

Journal Article J Biol Chem · November 9, 2001 beta-Arrestins are multifunctional adaptor proteins known to regulate internalization of agonist-stimulated G protein-coupled receptors by linking them to endocytic proteins such as clathrin and AP-2. Here we describe a previously unappreciated mechanism b ... Full text Link to item Cite

Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors.

Journal Article Nat Rev Neurosci · October 2001 In the classical model of G-protein-coupled receptor (GPCR) regulation, arrestins terminate receptor signalling. After receptor activation, arrestins desensitize phosphorylated GPCRs, blocking further activation and initiating receptor internalization. Thi ... Full text Link to item Cite

Beta-Arrestins: new roles in regulating heptahelical receptors' functions.

Journal Article Cell Signal · October 2001 The last few years have seen a marked expansion in appreciation of the diversity of roles played by the betaArrestins in regulating GPCR functions. Originally discovered as molecules that desensitize such receptors, the roles of betaArrestins have expanded ... Full text Link to item Cite

Altered bone mass and microarchitecture in beta-arrestin2 KO mice.

Journal Article JOURNAL OF BONE AND MINERAL RESEARCH · September 1, 2001 Link to item Cite

Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors.

Journal Article J Am Coll Cardiol · August 2001 OBJECTIVES: Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type alpha1B adrenergic receptor (AR) (Tg alpha43), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and its transiti ... Full text Link to item Cite

Identification of a motif in the carboxyl terminus of beta -arrestin2 responsible for activation of JNK3.

Journal Article J Biol Chem · July 27, 2001 Accumulating evidence indicates that the beta-arrestins act as scaffold molecules that couple G-protein-coupled receptors to mitogen-activated protein (MAP) kinase signaling pathways. Recently, we identified the c-Jun N-terminal kinase 3 (JNK3) as a beta-a ... Full text Link to item Cite

Epidermal growth factor (EGF) receptor-dependent ERK activation by G protein-coupled receptors: a co-culture system for identifying intermediates upstream and downstream of heparin-binding EGF shedding.

Journal Article J Biol Chem · June 22, 2001 "Transactivation" of epidermal growth factor receptors (EGFRs) in response to activation of many G protein-coupled receptors (GPCRs) involves autocrine/paracrine shedding of heparin-binding EGF (HB-EGF). HB-EGF shedding involves proteolytic cleavage of a m ... Full text Link to item Cite

Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.

Journal Article Proc Natl Acad Sci U S A · May 8, 2001 Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition ... Full text Open Access Link to item Cite

Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79.

Journal Article J Biol Chem · May 4, 2001 The beta2 adrenergic receptor (beta2AR) undergoes desensitization by a process involving its phosphorylation by both protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs). The protein kinase A-anchoring protein AKAP79 influences beta2AR phos ... Full text Link to item Cite

Expanding roles for beta-arrestins as scaffolds and adapters in GPCR signaling and trafficking.

Journal Article Curr Opin Cell Biol · April 2001 beta-arrestins play previously unsuspected and important roles as adapters and scaffolds that localize signaling proteins to ligand-activated G-protein-coupled receptors. As with the paradigmatic role of the beta-arrestins in uncoupling receptors from G pr ... Full text Link to item Cite

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

Journal Article J Clin Invest · April 2001 The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. ... Full text Open Access Link to item Cite

New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades.

Journal Article Oncogene · March 26, 2001 Activation of classical second messenger cascades cannot fully explain the recently appreciated roles of heptahelical, or G-protein coupled receptors (GPCRs), in stimulation of mitogen activated protein kinase (MAPK) cascades. Rather, several distinct sign ... Full text Link to item Cite

In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

Journal Article Circulation · March 6, 2001 BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase ( ... Full text Open Access Link to item Cite

Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.

Journal Article Proc Natl Acad Sci U S A · February 27, 2001 Using both confocal immunofluorescence microscopy and biochemical approaches, we have examined the role of beta-arrestins in the activation and targeting of extracellular signal-regulated kinase 2 (ERK2) following stimulation of angiotensin II type 1a rece ... Full text Open Access Link to item Cite

Arrestins as signaling molecules involved in apoptotic pathways: a real eye opener.

Journal Article Sci STKE · February 13, 2001 Recent data suggest that internalized receptor and arrestin complexes are actively involved in signal transduction. Miller and Lefkowitz discuss evidence from the Drosophila visual system that suggests that intracellular rhodopsin and arrestin2 complexes i ... Full text Link to item Cite

beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking.

Journal Article Proc Natl Acad Sci U S A · February 13, 2001 The two widely coexpressed isoforms of beta-arrestin (termed beta arrestin 1 and 2) are highly similar in amino acid sequence. The beta-arrestins bind phosphorylated heptahelical receptors to desensitize and target them to clathrin-coated pits for endocyto ... Full text Open Access Link to item Cite

Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.

Journal Article Proc Natl Acad Sci U S A · February 13, 2001 The goal of this study was to determine whether beta(1)-adrenergic receptor (AR) and beta(2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta(2)-AR can a ... Full text Open Access Link to item Cite

Prospects for cardiovascular research.

Journal Article JAMA · February 7, 2001 Cardiovascular disease is the greatest threat to human life and health. The past decade has seen remarkable progress in clinical and basic cardiovascular research, and many areas of opportunity are promising. The pace of current progress in clinical and ba ... Full text Link to item Cite

Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation.

Journal Article J Biol Chem · December 8, 2000 Both beta(2)- and beta(3)-adrenergic receptors (ARs) are able to activate the extracellular signal-regulated kinase (ERK) pathway. We previously showed that c-Src is required for ERK activation by beta(2)AR and that it is recruited to activated beta(2)AR t ... Full text Link to item Cite

beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors.

Journal Article J Biol Chem · December 8, 2000 The beta(1)-adrenergic receptor (beta(1)AR) is the most abundant subtype of beta-adrenergic receptor in the mammalian brain and is known to potently regulate synaptic plasticity. To search for potential neuronal beta(1)AR-interacting proteins, we screened ... Full text Link to item Cite

Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.

Journal Article Nature · December 7, 2000 Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate ... Full text Link to item Cite

β-Arrestin 2: A receptor-regulated MAPK scaffold for the activation of JNK3

Journal Article Science · November 24, 2000 β-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 ( ... Cite

Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.

Journal Article Science · November 24, 2000 beta-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase ... Full text Link to item Cite

Platelet-derived growth factor receptor association with Na(+)/H(+) exchanger regulatory factor potentiates receptor activity.

Journal Article Mol Cell Biol · November 2000 Platelet-derived growth factor (PDGF) is a potent mitogen for many cell types. The PDGF receptor (PDGFR) is a receptor tyrosine kinase that mediates the mitogenic effects of PDGF by binding to and/or phosphorylating a variety of intracellular signaling pro ... Full text Open Access Link to item Cite

Adenovirus-mediated genetic manipulation of the myocardial beta-adrenergic signaling system in transplanted hearts.

Journal Article J Thorac Cardiovasc Surg · September 2000 OBJECTIVES: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the beta-adrenergic receptor-signaling system, in w ... Full text Link to item Cite

The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing.

Journal Article J Biol Chem · July 21, 2000 We recently characterized a novel protein, GIT1, that interacts with G protein-coupled receptor kinases and possesses ADP-ribosylation factor (ARF) GTPase-activating protein activity. A second ubiquitously expressed member of the GIT protein family, GIT2, ... Full text Link to item Cite

Inhibition of spontaneous beta 2-adrenergic activation rescues beta 1-adrenergic contractile response in cardiomyocytes overexpressing beta 2-adrenoceptor.

Journal Article J Biol Chem · July 14, 2000 Cardiac-specific overexpression of the human beta(2)-adrenergic receptor (AR) in transgenic mice (TG4) enhances basal cardiac function due to ligand-independent spontaneous beta(2)-AR activation. However, agonist-mediated stimulation of either beta(1)-AR o ... Full text Link to item Cite

The superfamily of heptahelical receptors.

Journal Article Nat Cell Biol · July 2000 Despite a growing appreciation of functional analogies between visual and hormonal signalling systems in the early 1980s, the discovery of the close structural relationship between rhodopsin and the beta2-adrenergic receptor, and of the existence of a larg ... Full text Link to item Cite

alpha-Actinin is a potent regulator of G protein-coupled receptor kinase activity and substrate specificity in vitro.

Journal Article FEBS Lett · May 19, 2000 G protein-coupled receptor kinases (GRKs) phosphorylate G protein-coupled receptors, thereby terminating receptor signaling. Herein we report that alpha-actinin potently inhibits all GRK family members. In addition, calcium-bound calmodulin and phosphatidy ... Full text Link to item Cite

Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.

Journal Article Proc Natl Acad Sci U S A · May 9, 2000 When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated throu ... Full text Open Access Link to item Cite

GIT proteins, A novel family of phosphatidylinositol 3,4, 5-trisphosphate-stimulated GTPase-activating proteins for ARF6.

Journal Article J Biol Chem · May 5, 2000 ADP-ribosylation factor (ARF) proteins are key players in numerous vesicular trafficking events ranging from the formation and fusion of vesicles in the Golgi apparatus to exocytosis and endocytosis. To complete their GTPase cycle, ARFs require a guanine n ... Full text Link to item Cite

beta-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor endocytosis.

Journal Article J Biol Chem · April 14, 2000 beta-Arrestins can act as adapter molecules, coupling G-protein-coupled receptors to proteins involved in mitogenic as well as endocytic pathways. We have previously identified c-SRC as a molecule that is rapidly recruited to the beta2-adrenergic receptor ... Full text Link to item Cite

Assembly of an A kinase-anchoring protein-beta(2)-adrenergic receptor complex facilitates receptor phosphorylation and signaling.

Journal Article Curr Biol · April 6, 2000 Phosphorylation of G-protein-coupled receptors by second-messenger-stimulated kinases is central to the process of receptor desensitization [1-3]. Phosphorylation of the beta(2)-adrenergic receptor (beta(2)-AR) by protein kinase A (PKA), in addition to unc ... Full text Link to item Cite

The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor.

Journal Article J Biol Chem · March 31, 2000 Many G protein-coupled receptors (GPCRs) activate MAP kinases by stimulating tyrosine kinase signaling cascades. In some systems, GPCRs stimulate tyrosine phosphorylation by inducing the "transactivation" of a receptor tyrosine kinase (RTK). The mechanisms ... Full text Link to item Cite

Role of endocytosis in the activation of the extracellular signal-regulated kinase cascade by sequestering and nonsequestering G protein-coupled receptors.

Journal Article Proc Natl Acad Sci U S A · February 15, 2000 Acting through a number of distinct pathways, many G protein-coupled receptors (GPCRs) activate the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade. Recently, it has been shown that in some cases, clathrin-mediat ... Full text Open Access Link to item Cite

Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.

Journal Article Circulation · February 1, 2000 BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in tran ... Full text Open Access Link to item Cite

Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity.

Journal Article Proc Natl Acad Sci U S A · February 1, 2000 Recently, we identified a GTPase-activating protein for the ADP ribosylation factor family of small GTP-binding proteins that we call GIT1. This protein initially was identified as an interacting partner for the G protein-coupled receptor kinases, and its ... Full text Open Access Link to item Cite

Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart.

Journal Article Circ Res · January 7, 2000 G protein-coupled receptor kinases (GRKs) phosphorylate activated G protein-coupled receptors, including alpha(1B)-adrenergic receptors (ARs), resulting in desensitization. In vivo analysis of GRK substrate selectivity has been limited. Therefore, we gener ... Full text Open Access Link to item Cite

Functional consequences of altering myocardial adrenergic receptor signaling.

Journal Article Annu Rev Physiol · 2000 From the ability to successfully manipulate the mouse genome has come important transgenic and gene-targeted knockout models that impact many areas of biomedical research. Genetically engineered mouse models geared toward the study of cardiovascular regula ... Full text Link to item Cite

Enhanced morphine analgesia in mice lacking beta-arrestin 2.

Journal Article Science · December 24, 1999 The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the mu opioid receptor (muOR). The efficiency of GPCR signaling is tightly regulated and ult ... Full text Link to item Cite

Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases.

Journal Article J Biol Chem · December 3, 1999 G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and beta-arrestin binding uncouple G protein-coupled receptors (GPCRs) from their respective G proteins and initiates the process of receptor internalization. In the case of the beta ... Full text Link to item Cite

Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice.

Journal Article Neuron · December 1999 G protein-coupled receptor kinase 5 (GRK5) is a member of a family of enzymes that phosphorylate activated G protein-coupled receptors (GPCR). To address the physiological importance of GRK5-mediated regulation of GPCRs, mice bearing targeted deletion of t ... Full text Link to item Cite

Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury.

Journal Article Circ Res · November 26, 1999 Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the ... Full text Open Access Link to item Cite

Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · October 26, 1999 Several G-protein coupled receptors, such as the beta1-adrenergic receptor (beta1-AR), contain polyproline motifs within their intracellular domains. Such motifs in other proteins are known to mediate protein-protein interactions such as with Src homology ... Full text Open Access Link to item Cite

The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation.

Journal Article J Biol Chem · October 8, 1999 G protein-coupled receptor kinases (GRKs) desensitize G protein-coupled receptors by phosphorylating activated receptors. The six known GRKs have been classified into three subfamilies based on sequence and functional similarities. Examination of the mouse ... Full text Link to item Cite

G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction.

Journal Article J Biol Chem · August 20, 1999 The Na(+)/H(+) exchanger regulatory factor (NHERF) is constitutively phosphorylated in cells, but the site(s) of this phosphorylation and the kinase(s) responsible for it have not been identified. We show here that the primary site of constitutive NHERF ph ... Full text Link to item Cite

In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function.

Journal Article Circulation · August 10, 1999 BACKGROUND: The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac beta-adrenergic receptor (betaAR) system, which is critical in the regulation of myocardial function. Expression of the betaAR kinase (betaARK1), which phosphor ... Full text Open Access Link to item Cite

Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.

Journal Article J Clin Invest · July 1999 Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient an ... Full text Open Access Link to item Cite

Adenovirus-mediated gene transfer of the beta2-adrenergic receptor to donor hearts enhances cardiac function.

Journal Article Gene Ther · July 1999 Gene transfer to modify donor heart function during transplantation has significant therapeutic implications. Recent studies by our laboratory in transgenic mice have shown that overexpression of beta2-adrenergic receptors (beta2-ARs) leads to significantl ... Full text Link to item Cite

Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases.

Journal Article J Biol Chem · June 4, 1999 The functions of beta-arrestin1 to facilitate clathrin-mediated endocytosis of the beta2-adrenergic receptor and to promote agonist-induced activation of extracellular signal-regulated kinases (ERK) are regulated by its phosphorylation/dephosphorylation at ... Full text Link to item Cite

Hetahelical receptor signaling: Beyond the G protein paradigm

Journal Article Journal of Cell Biology · May 31, 1999 Full text Cite

Pleiotropic coupling of G protein-coupled receptors to the mitogen-activated protein kinase cascade. Role of focal adhesions and receptor tyrosine kinases.

Journal Article J Biol Chem · May 14, 1999 G protein-coupled receptors (GPCRs) initiate Ras-dependent activation of the Erk 1/2 mitogen-activated protein kinase cascade by stimulating recruitment of Ras guanine nucleotide exchange factors to the plasma membrane. Both integrin-based focal adhesion c ... Full text Link to item Cite

Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation.

Journal Article J Biol Chem · April 16, 1999 Previous studies have demonstrated that beta-arrestin1 serves to target G protein-coupled receptors for internalization via clathrin-coated pits and that its endocytic function is regulated by dephosphorylation at the plasma membrane. Using the yeast two-h ... Full text Link to item Cite

β-drenergic receptor overexpression in the developing mouse heart: Evidence for targeted modulation of ion channels

Journal Article Journal of Physiology · April 1, 1999 1. We studied the effect of overexpression of the β2-adrenergic receptor (β2-AR) in the heart on ion channel currents in single cells isolated from hearts of fetal and neonatal transgenic and wild-type mice. The β2-AR transgene construct was under the cont ... Full text Cite

Regulation of tyrosine kinase cascades by G-protein-coupled receptors.

Journal Article Curr Opin Cell Biol · April 1999 Mitogenic signaling by G-protein-coupled receptors (GPCRs) involves tyrosine phosphorylation of adaptor proteins and assembly of multiprotein Ras activation complexes. Over the past three years, three types of scaffolds for GPCR-directed complex assembly h ... Full text Link to item Cite

Beta2-adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels.

Journal Article J Physiol · April 1, 1999 1. We studied the effect of overexpression of the beta2-adrenergic receptor (beta2-AR) in the heart on ion channel currents in single cells isolated from hearts of fetal and neonatal transgenic and wild-type mice. The beta2-AR transgene construct was under ... Full text Link to item Cite

Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.

Journal Article Proc Natl Acad Sci U S A · March 30, 1999 Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidate ... Full text Open Access Link to item Cite

Serotonin 5-HT1A receptor-mediated Erk activation requires calcium/calmodulin-dependent receptor endocytosis.

Journal Article J Biol Chem · February 19, 1999 Many receptors that couple to heterotrimeric guanine nucleotide-binding (G) proteins mediate rapid activation of the mitogen-activated protein kinases, Erk1 and Erk2. The Gi-coupled serotonin (5-hydroxytryptamine (5-HT)) 5-HT1A receptor, heterologously exp ... Full text Link to item Cite

Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.

Journal Article Science · January 29, 1999 The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of beta2 adrene ... Full text Link to item Cite

Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signaling.

Journal Article J Biol Chem · January 15, 1999 Some forms of G protein-coupled receptor signaling, such as activation of mitogen-activated protein kinase cascade as well as resensitization of receptors after hormone-induced desensitization, require receptor internalization via dynamin-dependent clathri ... Full text Link to item Cite

Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes.

Journal Article Circ Res · January 8, 1999 -Transgenic mouse models have been developed to manipulate beta-adrenergic receptor (betaAR) signal transduction. Although several of these models have altered betaAR subtypes, the specific functional sequelae of betaAR stimulation in murine heart, particu ... Full text Open Access Link to item Cite

Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation.

Journal Article Hypertension · January 1999 Pressure overload ventricular hypertrophy is accompanied by dysfunctional beta-adrenergic receptor signaling due to increased levels of the beta-adrenergic receptor kinase-1, which phosphorylates and desensitizes beta-adrenergic receptors. In this study, w ... Full text Open Access Link to item Cite

Myocardial G protein-coupled receptor kinases: implications for heart failure therapy.

Journal Article Proc Assoc Am Physicians · 1999 The beta-adrenergic signaling cascade is an important regulator of myocardial function. Significant alterations of this pathway are associated with several cardiovascular diseases, including congestive heart failure (CHF). Included in these alterations is ... Full text Link to item Cite

beta-arrestins regulate mitogenic signaling and clathrin-mediated endocytosis of the insulin-like growth factor I receptor.

Journal Article J Biol Chem · November 27, 1998 beta-Arrestins mediate agonist-dependent desensitization of G protein-coupled receptors and target the receptors to clathrin-coated pits for internalization. Here we report an expanded role of beta-arrestins in promoting clathrin-mediated endocytosis of a ... Full text Link to item Cite

beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein.

Journal Article Proc Natl Acad Sci U S A · November 24, 1998 G protein-coupled receptor activation leads to the membrane recruitment and activation of G protein-coupled receptor kinases, which phosphorylate receptors and lead to their inactivation. We have identified a novel G protein-coupled receptor kinase-interac ... Full text Open Access Link to item Cite

Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6.

Journal Article Biochemistry · November 17, 1998 The G protein-coupled receptor kinase GRK6 undergoes posttranslational modification by palmitoylation. Palmitoylated GRK6 is associated with the membrane, while nonpalmitoylated GRK6 remains cytosolic. We have separated palmitoylated from nonpalmitoylated ... Full text Link to item Cite

Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade.

Journal Article Circulation · October 27, 1998 BACKGROUND: Impaired myocardial beta-adrenergic receptor (betaAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial ... Full text Open Access Link to item Cite

Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin.

Journal Article J Biol Chem · August 7, 1998 G protein-coupled receptor kinases (GRKs) initiate pathways leading to the desensitization of agonist-occupied G-protein-coupled receptors (GPCRs). Here we report that the cytoskeletal protein actin binds and inhibits GRK5. Actin inhibits the kinase activi ... Full text Link to item Cite

G protein signaling and vein graft intimal hyperplasia: reduction of intimal hyperplasia in vein grafts by a Gbetagamma inhibitor suggests a major role of G protein signaling in lesion development.

Journal Article Arterioscler Thromb Vasc Biol · August 1998 Vein grafting results in the development of intimal hyperplasia with accompanying changes in guanine nucleotide-binding (G) protein expression and function. Several serum mitogens that act through G protein-coupled receptors, such as lysophosphatidic acid, ... Full text Open Access Link to item Cite

A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins.

Journal Article Proc Natl Acad Sci U S A · July 21, 1998 The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta ... Full text Open Access Link to item Cite

Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice.

Journal Article J Biol Chem · July 17, 1998 We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only hetero ... Full text Link to item Cite

GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain.

Journal Article J Biol Chem · July 10, 1998 Regulator of G-protein signaling (RGS) proteins increase the intrinsic guanosine triphosphatase (GTPase) activity of G-protein alpha subunits in vitro, but how specific G-protein-coupled receptor systems are targeted for down-regulation by RGS proteins rem ... Full text Link to item Cite

Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Journal Article Proc Natl Acad Sci U S A · June 9, 1998 Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is ... Full text Open Access Link to item Cite

Molecular basis for interactions of G protein betagamma subunits with effectors.

Journal Article Science · May 22, 1998 Both the alpha and betagamma subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins) communicate signals from receptors to effectors. Gbetagamma subunits can regulate a diverse array of effectors, including ion channels and enzymes. Gal ... Full text Link to item Cite

The G protein-coupled receptor kinase 2 is a microtubule-associated protein kinase that phosphorylates tubulin.

Journal Article J Biol Chem · May 15, 1998 The G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase that phosphorylates and desensitizes agonist-occupied G protein-coupled receptors (GPCRs). Here we demonstrate that GRK2 is a microtubule-associated protein and identify tubulin as ... Full text Link to item Cite

Enhanced vasorelaxation by overexpression of beta 2-adrenergic receptors in large arteries.

Journal Article J Mol Cell Cardiol · May 1998 This study was designed to determine if adenoviral-mediated delivery of a transgene encoding the beta 2-adrenergic receptor (beta 2-AR) to the carotid arterial wall could result in alterations in in vivo vascular function. De-endothelialized rat carotid ar ... Full text Link to item Cite

Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy.

Journal Article Science · April 24, 1998 Hormones and neurotransmitters may mediate common responses through receptors that couple to the same class of heterotrimeric guanine nucleotide-binding (G) protein. For example, several receptors that couple to Gq class proteins can induce cardiomyocyte h ... Full text Link to item Cite

The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange.

Journal Article Nature · April 9, 1998 Stimulation of beta2-adrenergic receptors on the cell surface by adrenaline or noradrenaline leads to alterations in the metabolism, excitability, differentiation and growth of many cell types. These effects have traditionally been thought to be mediated e ... Full text Link to item Cite

Mutagenesis of acidic residues in the β2-adrenergic receptor abolishes the requirement of low pH for receptor dephosphorylation

Journal Article FASEB Journal · March 20, 1998 We have previously shown that acidic pH activates β2-adrenergic receptor (B2AR) dephosphorylation both in vitro as well as in cells, where sequestered B2ARs are localized to endosomes. To further define the role of acidic pH in receptor dephosphorylation, ... Cite

Ex vivo adenovirus-mediated gene transfer to the adult rat heart.

Journal Article J Thorac Cardiovasc Surg · March 1998 OBJECTIVE: The ability to transfer genes to adult myocardium may have therapeutic implications for cardiac transplantation. We investigated the feasibility of adenovirus-mediated transfer of marker genes LacZ and Luciferase, as well as the potentially ther ... Full text Link to item Cite

Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase.

Journal Article J Biol Chem · January 9, 1998 The classical paradigm for G protein-coupled receptor (GPCR) signal transduction involves the agonist-dependent interaction of GPCRs with heterotrimeric G proteins at the plasma membrane and the subsequent generation, by membrane-localized effectors, of so ... Full text Link to item Cite

G protein-coupled receptor kinases.

Journal Article Annu Rev Biochem · 1998 G protein-coupled receptor kinases (GRKs) constitute a family of six mammalian serine/threonine protein kinases that phosphorylate agonist-bound, or activated, G protein-coupled receptors (GPCRs) as their primary substrates. GRK-mediated receptor phosphory ... Full text Link to item Cite

Altered cardiac chronotropic responses in βARK 2 knockout mice

Journal Article FASEB Journal · 1998 G protein-coupled receptor kinases (GRKs) desensitize agonist-activated G protein-coupled receptors (GPCRs) thus attenuating their responses. In cell culture experiments, GRK 3 (βARK 2) phosphorylates and desensitizes multiple GPCRs, including muscarinic a ... Cite

New paradigms for G protein-coupled receptor signaling and desensitization.

Journal Article NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY · January 1, 1998 Link to item Cite

G protein-coupled receptor kinase 5 in cultured vascular smooth muscle cells and rat aorta. Regulation by angiotensin II and hypertension.

Journal Article J Biol Chem · December 19, 1997 GRK5, a recently cloned member of the G protein-coupled receptor kinase family, has been shown to phosphorylate and participate in the desensitization of angiotensin II (Ang II) type 1A (AT1A) receptors. In this study, the effect of angiotensin II on GRK5 ... Full text Link to item Cite

G protein-coupled receptors mediate two functionally distinct pathways of tyrosine phosphorylation in rat 1a fibroblasts. Shc phosphorylation and receptor endocytosis correlate with activation of Erk kinases.

Journal Article J Biol Chem · December 12, 1997 The Ras-dependent activation of Erk kinases by G protein-coupled receptors (GPCRs) is thought to involve tyrosine phosphorylation of docking proteins that serve as scaffolds for the plasma membrane recruitment of Ras guanine nucleotide exchange factors, su ... Full text Link to item Cite

Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1.

Journal Article J Biol Chem · December 5, 1997 beta-Arrestins serve a dual regulatory role in the life cycle of G protein-coupled receptors such as the beta2-adrenergic receptor. First, they mediate rapid desensitization by binding to G protein-coupled receptor kinase-phosphorylated receptors. Second, ... Full text Link to item Cite

Molecular basis for gβγ-effector interaction: Structural correlation with ga binding site

Conference FASEB Journal · December 1, 1997 This work is a collaborative study by several laboratories directed at localizing sites of interaction between Gβγ, an important mediator of transmembrane signaling, and numerous downstream partners. To this end we have targeted residues on Gβγ that contac ... Cite

G protein-coupled receptors and their regulation

Journal Article FASEB Journal · December 1, 1997 Seven membrane spanning domain G protein-coupled receptors represent the most ubiquitous and diverse group of membrane bound signaling receptors. Their function is regulated by two families of molecules, the G protein-coupled receptor kinases and the ß-arr ... Cite

Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A.

Journal Article Nature · November 6, 1997 Many of the G-protein-coupled receptors for hormones that bind to the cell surface can signal to the interior of the cell through several different classes of G protein. For example, although most of the actions of the prototype beta2-adrenergic receptor a ... Full text Link to item Cite

Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer.

Journal Article Proc Natl Acad Sci U S A · October 28, 1997 Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. ... Full text Open Access Link to item Cite

G protein-coupled receptor kinase 3 (GRK3) gene disruption leads to loss of odorant receptor desensitization.

Journal Article J Biol Chem · October 10, 1997 G protein-coupled receptor kinases (GRKs) 2 and 3 (beta-adrenergic receptor kinases 1 and 2 (betaARK1 and -2)) mediate the agonist-dependent phosphorylation and uncoupling of many G protein-coupled receptors. These two members of the GRK family share a hig ... Full text Link to item Cite

Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling.

Journal Article J Biol Chem · August 22, 1997 Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha1B-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter. Previously, we described transgenic mice with alpha-myosin heavy chain-direc ... Full text Link to item Cite

Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase.

Journal Article J Biol Chem · August 1, 1997 Many receptors that couple to heterotrimeric guanine-nucleotide binding proteins (G proteins) have been shown to mediate rapid activation of the mitogen-activated protein kinases Erk1 and Erk2. In different cell types, the signaling pathways employed appea ... Full text Link to item Cite

Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity.

Journal Article J Biol Chem · July 11, 1997 Although endothelin-1 can elicit prolonged physiologic responses, accumulating evidence suggests that rapid desensitization affects the primary G protein-coupled receptors mediating these responses, the endothelin A and B receptors (ETA-R and ETB-R). The m ... Full text Link to item Cite

Gene transfer strategies for augmenting cardiac function.

Journal Article Trends Cardiovasc Med · July 1997 Recent transgenic as well as gene-targeted animal models have greatly increased our understanding of the molecular mechanisms of normal and compromised heart function. These studies have raised the possibility of using somatic gene transfer as a means for ... Full text Link to item Cite

Synergistic regulation of beta2-adrenergic receptor sequestration: intracellular complement of beta-adrenergic receptor kinase and beta-arrestin determine kinetics of internalization.

Journal Article Mol Pharmacol · May 1997 Two of the common mechanisms regulating G protein-coupled receptor (GPCR) signal transduction are phosphorylation and sequestration (internalization). Agonist-mediated receptor phosphorylation by the beta-adrenergic receptor kinase (betaARK) facilitates su ... Link to item Cite

Potentiation of beta-adrenergic signaling by gene transfer.

Journal Article Proc Assoc Am Physicians · May 1997 The beta-adrenergic signaling cascade is an important regulator of myocardial function. Numerous abnormalities occur in this pathway and are associated with impaired cardiac contractility in patients with congestive heart failure (CHF). These signaling def ... Link to item Cite

Receptor and G betagamma isoform-specific interactions with G protein-coupled receptor kinases.

Journal Article Proc Natl Acad Sci U S A · March 18, 1997 The G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate and desensitize agonist-occupied GPCRs. GRK2-mediated receptor phosphorylation is preceded by the agonist-dependent membrane association of this enzyme. Previous in vitro studies with purif ... Full text Open Access Link to item Cite

Functional analysis of myocardial performance in murine hearts overexpressing the human beta 2-adrenergic receptor.

Journal Article J Mol Cell Cardiol · March 1997 Transgenic mice overexpressing the human beta 2-adrenergic receptor gene were compared with wild mice type in terms of cardiac function, using a modified work-performing isolated murine heart preparation and on-line computer analysis. A preload-dependent e ... Full text Link to item Cite

Transgenic manipulation of β-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine

Journal Article American Journal of Physiology - Heart and Circulatory Physiology · February 20, 1997 To determine the direct functional significance of the β-adrenergic receptor (AR) kinase 1 (βARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to acute β1 ... Cite

Gbetagamma subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation.

Journal Article J Biol Chem · February 14, 1997 In many cells, stimulation of mitogen-activated protein kinases by both receptor tyrosine kinases and receptors that couple to pertussis toxin-sensitive heterotrimeric G proteins proceed via convergent signaling pathways. Both signals are sensitive to inhi ... Full text Link to item Cite

Phosducin, potential role in modulation of olfactory signaling.

Journal Article J Biol Chem · February 14, 1997 Phosducin, which tightly binds betagamma-subunits of heterotrimeric G-proteins, has been conjectured to play a role in regulating second messenger signaling cascades, but to date its specific function has not been elucidated. Here we demonstrate a potentia ... Full text Link to item Cite

Potentiation of beta-adrenergic signaling by adenoviral-mediated gene transfer in adult rabbit ventricular myocytes.

Journal Article J Clin Invest · January 15, 1997 Our laboratory has been testing the hypothesis that genetic modulation of the beta-adrenergic signaling cascade can enhance cardiac function. We have previously shown that transgenic mice with cardiac overexpression of either the human beta2-adrenergic rec ... Full text Open Access Link to item Cite

Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

Journal Article Proc Natl Acad Sci U S A · January 7, 1997 Transgenic overexpression (40- to 100-fold) of the wild-type human beta2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) acti ... Full text Open Access Link to item Cite

The role of sequestration in G protein-coupled receptor resensitization. Regulation of beta2-adrenergic receptor dephosphorylation by vesicular acidification.

Journal Article J Biol Chem · January 3, 1997 G protein-coupled receptor kinases phosphorylate the agonist occupied conformation of G protein-coupled receptors in the plasma membrane, leading to their desensitization. Receptor resensitization requires receptor dephosphorylation, a process which is med ... Full text Link to item Cite

Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization.

Journal Article Recept Channels · 1997 Dynamic regulation of G protein-coupled receptor signaling demands a coordinated balance between mechanisms leading to the generation, turning off and re-establishment of agonist-mediated signals. G protein-coupled receptor kinases (GRKs) and arrestin prot ... Link to item Cite

Costimulation of adenylyl cyclase and phospholipase C by a mutant alpha 1B-adrenergic receptor transgene promotes malignant transformation of thyroid follicular cells.

Journal Article Endocrinology · January 1997 Proliferation of thyroid follicular cells is controlled by three intra-cellular cascades [cAMP, inositol 1,4,5-triphosphate (IP3)/Ca2+/diacylglycerol (DAG), and tyrosine kinases] that are activated by distinct extracellular signals and receptors. We had pr ... Full text Open Access Link to item Cite

G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors.

Journal Article Adv Second Messenger Phosphoprotein Res · 1997 G-protein-coupled receptors that mediate cellular responses to a variety of humoral, endothelial-, or platelet-derived substances are able to stimulate MAP kinase activity. In transfected model systems, G-protein-coupled receptors that couple to pertussis ... Link to item Cite

Cloning, characterization, and chromosomal localization of rec1.3, a member of the G-protein-coupled receptor family highly expressed in brain.

Journal Article Brain Res Mol Brain Res · December 1996 During a project to identify G-protein-coupled receptors (GPCR) expressed within taste buds, we have isolated a novel receptor-like sequence. The full length sequence of this receptor (rec1.3) has been obtained in both cow and mouse. Rec1.3 bears little se ... Full text Link to item Cite

Functional interaction between angiotensin ii and grk5 in cultured vascular smooth muscle cells (vsmc) and rat aorta

Journal Article FASEB Journal · December 1, 1996 G protein receptor kinases (GRKs) are involved in receptor desensitization. In HEK293 cells overexpressing the angiotensin II (ang U) ATiA receptor (ATjAR) and GRK5, the ATjAR is a substrate for GRK5 and coupling to phospholipase C (PLC) is diminished. In ... Cite

Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.

Journal Article Proc Natl Acad Sci U S A · November 12, 1996 The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors. We have cloned and disrupted the bet ... Full text Open Access Link to item Cite

Ras-dependent activation of fibroblast mitogen-activated protein kinase by 5-HT1A receptor via a G protein beta gamma-subunit-initiated pathway.

Journal Article Biochemistry · October 29, 1996 Serotonin (5-HT) is a potent mitogen in many cells types, an action which is frequently mediated through pertussis toxin-sensitive G proteins. In the current study, we used pharmacological inhibitors and dominant negative signaling constructs to delineate ... Full text Link to item Cite

Phosphatidylinositol 4,5-bisphosphate (PIP2)-enhanced G protein-coupled receptor kinase (GRK) activity. Location, structure, and regulation of the PIP2 binding site distinguishes the GRK subfamilies.

Journal Article J Biol Chem · October 4, 1996 The G protein-coupled receptor kinases (GRKs) phosphorylate agonist occupied G protein-coupled receptors and play an important role in mediating receptor desensitization. The localization of these enzymes to their membrane incorporated substrates is requir ... Full text Link to item Cite

Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice.

Journal Article Proc Natl Acad Sci U S A · September 3, 1996 Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled receptor kinase-5 (GRK5), a serine/threonine kinase most abundantly expressed in the heart compared with other tissues. Animals overexpressing GRK5 showed marked b ... Full text Open Access Link to item Cite

Myocardial beta-adrenergic receptor signaling in vivo: insights from transgenic mice.

Journal Article J Mol Med (Berl) · September 1996 Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor ... Full text Link to item Cite

Divergent pertussis toxin-sensitive pathways for 5-HT1A receptor activation of NHE & ERK

Journal Article JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY · September 1, 1996 Link to item Cite

Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gbetagamma subunit-mediated activation of mitogen-activated protein kinases.

Journal Article J Biol Chem · August 9, 1996 Several G protein-coupled receptors that interact with pertussis toxin-sensitive heterotrimeric G proteins mediate Ras-dependent activation of mitogen-activated protein (MAP) kinases. The mechanism involves Gbetagamma subunit-mediated increases in tyrosine ... Full text Link to item Cite

Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases.

Journal Article Proc Natl Acad Sci U S A · July 23, 1996 Guanine nucleotide-binding regulatory protein (G protein)-coupled receptor kinases (GRKs) constitute a family of serine/threonine kinases that play a major role in the agonist-induced phosphorylation and desensitization of G-protein-coupled receptors. Here ... Full text Open Access Link to item Cite

The third beta is not the charm.

Journal Article J Clin Invest · July 15, 1996 Full text Open Access Link to item Cite

Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor.

Journal Article J Biol Chem · June 7, 1996 Rapid desensitization of G protein-coupled receptors is mediated, at least in part, by their phosphorylation by the G protein-coupled receptor kinases (GRKs). However, only in the case of rhodopsin have the actual sites of receptor phosphorylation been una ... Full text Link to item Cite

Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C.

Journal Article J Biol Chem · May 31, 1996 The type 1A angiotensin II receptor (AT1A-R), which mediates cardiovascular effects of angiotensin II, has been shown to undergo rapid agonist-induced desensitization. We investigated the potential role of second messenger-activated kinases and G protein-c ... Full text Link to item Cite

Phosphatidylinositol 3-kinase is an early intermediate in the G beta gamma-mediated mitogen-activated protein kinase signaling pathway.

Journal Article J Biol Chem · May 24, 1996 The beta gamma-subunit of Gi mediates mitogen-activated protein (MAP) kinase activation through a signaling pathway involving Shc tyrosine phosphorylation, subsequent formation of a multiprotein complex including Shc, Grb2, and Sos, and sequential activati ... Full text Link to item Cite

Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration.

Journal Article Biochemistry · April 2, 1996 We recently reported that a beta2-adrenergic receptor (beta2AR) mutant, Y326A, defective in its ability to sequester in response to agonist stimulation was a poor substrate for G protein-coupled receptor kinase (GRK)-mediated phosphorylation; however, its ... Full text Link to item Cite

Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta2-adrenergic receptor is associated with reduced phospholamban protein.

Journal Article J Clin Invest · April 1, 1996 To assess the effect of targeted myocardial beta-adrenergic receptor (AR) stimulation on relaxation and phospholamban regulation, we studied the physiological and biochemical alterations associated with overexpression of the human beta2-AR gene in transgen ... Full text Open Access Link to item Cite

Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants.

Journal Article J Biol Chem · March 15, 1996 A novel human G protein-coupled receptor kinase was recently identified by positional cloning in the search for the Huntington's disease locus (Ambrose, C., James, M., Barnes, G., Lin, C., Bates, G., Altherr, M., Duyao, M., Groot, N., Church, D., Wasmuth, ... Full text Link to item Cite

G protein-coupled receptor kinase mediates desensitization of norepinephrine-induced Ca2+ channel inhibition.

Journal Article Neuron · March 1996 G protein-coupled receptors are essential signaling molecules at sites of synaptic transmission. Here, we explore the mechanisms responsible for the use-dependent termination of metabotropic receptor signaling in embryonic sensory neurons. We report that t ... Full text Link to item Cite

Differential regulation of dopamine D1A receptor responsiveness by various G protein-coupled receptor kinases.

Journal Article J Biol Chem · February 16, 1996 The role of G protein-coupled receptor kinases (GRKs) in the regulation of dopamine D1A receptor responsiveness is poorly understood. To explore the potential role played by the GRKs in the regulation of the rat dopamine D1A receptor, we performed whole ce ... Full text Link to item Cite

G(o)-protein alpha-subunits activate mitogen-activated protein kinase via a novel protein kinase C-dependent mechanism.

Journal Article J Biol Chem · January 19, 1996 Mitogen-activated protein kinase (MAPK) is activated in response to both receptor tyrosine kinases and G-protein-coupled receptors. Recently, Gi-coupled receptors, such as the alpha 2A adrenergic receptor, were shown to mediate Ras-dependent MAPK activatio ... Full text Link to item Cite

Production of adrenergic receptors in yeast.

Journal Article Recept Channels · 1996 Using a recombinant yeast strain expressing human beta 2 adrenergic receptors under a galactose-inducible promoter, we established conditions for receptor production in 1-15 liter fermenter culture. Crucial factors contributing to consistent high-level exp ... Link to item Cite

Desensitization of G protein-coupled receptors.

Journal Article Recent Prog Horm Res · 1996 Waning responsiveness to continuous or repeated stimulation constitutes the phenomenon of desensitization, which pervades biological systems. Over the last several years, molecular mechanisms for desensitization of cellular signaling through G protein-coup ... Link to item Cite

Go-protein α-subunits activate mitogen-activated protein kinase via a novel protein kinase C-dependent mechanism

Journal Article Journal of Biological Chemistry · 1996 Mitogen-activated protein kinase (MAPK) is activated in response to both receptor tyrosine kinases and G-protein-coupled receptors. Recently, Gi-coupled receptors, such as the α2A adrenergic receptor, were shown to mediate Ras-dependent MAPK activation via ... Cite

An essential role for src tyrosine kinase/shc adapter protein complexes in gβy subunit-mediated mitogen-activated protein kinase activation

Journal Article Journal of Investigative Medicine · January 1, 1996 Several G protein-coupled recepiors which interact with pertussis toxin-sensitive heterotrimenc G proteins mediate Ras-dependent activation of mitogen-activated protein (MAP) kinases. The mechanism involves Gβysubunit-mediated increases in tyrosine phospho ... Cite

Immunoaffinity purification of epitope-tagged human beta 2-adrenergic receptor to homogeneity.

Journal Article Protein Expr Purif · December 1995 To obtain large quantities of pure human beta 2-adrenergic receptor (beta 2-AR) needed for structural studies, an efficient method for beta 2-AR purification was developed using a recombinant receptor with an eight amino acid epitope at its C-terminus. Thi ... Full text Link to item Cite

G protein beta gamma subunits stimulate phosphorylation of Shc adapter protein.

Journal Article Proc Natl Acad Sci U S A · September 26, 1995 The mechanism of mitogen-activated protein (MAP) kinase activation by pertussis toxin-sensitive Gi-coupled receptors is known to involve the beta gamma subunits of heterotrimeric G proteins (G beta gamma), p21ras activation, and an as-yet-unidentified tyro ... Full text Open Access Link to item Cite

Receptor-tyrosine-kinase- and G beta gamma-mediated MAP kinase activation by a common signalling pathway.

Journal Article Nature · August 31, 1995 Mitogen-activated protein (MAP) kinases mediate the phosphorylation and activation of nuclear transcription factors that regulate cell growth. MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrin ... Full text Link to item Cite

The G-protein-coupled receptor phosphatase: a protein phosphatase type 2A with a distinct subcellular distribution and substrate specificity.

Journal Article Proc Natl Acad Sci U S A · August 29, 1995 Phosphorylation of G-protein-coupled receptors plays an important role in regulating their function. In this study the G-protein-coupled receptor phosphatase (GRP) capable of dephosphorylating G-protein-coupled receptor kinase-phosphorylated receptors is d ... Full text Open Access Link to item Cite

Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C.

Journal Article Mol Pharmacol · August 1995 With chronic opiate use, opioid receptor desensitization may be one of the important mechanisms underlying the development of opiate tolerance and addiction. Opioid receptors belong to the G protein-coupled receptor superfamily. In this study, the mouse de ... Link to item Cite

Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase.

Journal Article J Biol Chem · July 28, 1995 Persistent stimulation of the beta 1-adrenergic receptor (beta 1AR) engenders, within minutes, diminished responsiveness of the beta 1 AR/adenylyl cyclase signal transduction system. This desensitization remains incompletely defined mechanistically, howeve ... Full text Link to item Cite

Ca(2+)-dependent interaction of recoverin with rhodopsin kinase.

Journal Article J Biol Chem · July 28, 1995 Recoverin (Rv) is a myristoylated Ca(2+)-binding protein present primarily in bovine photoreceptors. It represents a newly identified family of neuronal specific Ca(2+)-binding proteins that includes neurocalcin, hippocalcin, and guanylyl cyclase-activatin ... Full text Link to item Cite

Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation.

Journal Article J Biol Chem · July 21, 1995 Receptors that couple to the heterotrimeric G proteins, Gi or Gq, can stimulate phosphoinositide (PI) hydrolysis and mitogen-activated protein kinase (MAPK) activation. PI hydrolysis produces inositol 1,4,5-trisphosphate and diacylglycerol, leading to acti ... Full text Link to item Cite

Mutational analysis of the pleckstrin homology domain of the beta-adrenergic receptor kinase. Differential effects on G beta gamma and phosphatidylinositol 4,5-bisphosphate binding.

Journal Article J Biol Chem · July 14, 1995 The beta gamma subunits of heterotrimeric G proteins (G beta gamma) play a variety of roles in cellular signaling, one of which is membrane targeting of the beta-adrenergic receptor kinase (beta ARK). This is accomplished via a physical interaction of G be ... Full text Link to item Cite

G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor.

Journal Article J Biol Chem · July 14, 1995 The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stim ... Full text Link to item Cite

Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor.

Journal Article Science · June 2, 1995 Transgenic mice were created with cardiac-specific overexpression of the beta-adrenergic receptor kinase-1 (beta ARK1) or a beta ARK inhibitor. Animals overexpressing beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contracti ... Full text Link to item Cite

Effect of cellular expression of pleckstrin homology domains on Gi-coupled receptor signaling.

Journal Article J Biol Chem · June 2, 1995 Pleckstrin homology (PH) domains are 90-110 amino acid regions of protein sequence homology that are found in a variety of proteins involved in signal transduction and growth control. We have previously reported that the PH domains of several proteins, inc ... Full text Link to item Cite

A region of adenylyl cyclase 2 critical for regulation by G protein beta gamma subunits.

Journal Article Science · May 26, 1995 Receptor-mediated activation of heterotrimeric guanine nucleotide-binding proteins (G proteins) results in the dissociation of alpha from beta gamma subunits, thereby allowing both to regulate effectors. Little is known about the regions of effectors requi ... Full text Link to item Cite

Pleckstrin homology domain-mediated membrane association and activation of the beta-adrenergic receptor kinase requires coordinate interaction with G beta gamma subunits and lipid.

Journal Article J Biol Chem · May 19, 1995 The pleckstrin homology (PH) domain is an approximately 100-amino-acid region of sequence homology present in numerous proteins of diverse functions, which forms a discrete structural module. Several ligands capable of binding to PH domain-containing prote ... Full text Link to item Cite

Cardiac muscarinic potassium channel activity is attenuated by inhibitors of G beta gamma.

Journal Article Circ Res · May 1995 The cardiac muscarinic potassium channel (IK.ACh) is activated by a G protein upon receptor stimulation with acetylcholine. The G protein subunit responsible for activation (G alpha versus G beta gamma) has been disputed. We used G beta gamma inhibitors de ... Full text Link to item Cite

G beta gamma interactions with PH domains and Ras-MAPK signaling pathways.

Journal Article Trends Biochem Sci · April 1995 G-protein-coupled receptor signaling and receptor tyrosine kinase (RTK) signaling are two mechanisms of transmembrane communication used by numerous extracellular agents and stimuli. The beta gamma-subunit complex of G proteins mediates many of the functio ... Full text Link to item Cite

Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor.

Journal Article Nature · March 16, 1995 G-protein-coupled receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling. But new evidence suggests a two-state model in which receptors are in equilibrium between the ... Full text Link to item Cite

Marked enhancement in myocardial function resulting from overexpression of a human beta-adrenergic receptor gene.

Journal Article J Thorac Cardiovasc Surg · February 1995 Transgenic mice with intense cardiac expression of a human beta-adrenergic receptor gene were engineered and shown to display marked improvements in baseline myocardial and left ventricular function. Heart/body weight ratios and histologic appearance were ... Full text Link to item Cite

Protein kinases that phosphorylate activated G protein-coupled receptors.

Journal Article FASEB J · February 1995 G protein-coupled receptor kinases (GRKs) are a family of serine/threonine protein kinases that specifically recognize agonist-occupied, activated G protein-coupled receptor proteins as substrates. Phosphorylation of an activated receptor by a GRK terminat ... Full text Link to item Cite

MECHANISMS OF DESENSITIZATION IN OLFACTION

Journal Article CHEMICAL SENSES · February 1, 1995 Link to item Cite

G proteins in medicine.

Journal Article N Engl J Med · January 19, 1995 Full text Open Access Link to item Cite

Odorant receptors and desensitization proteins colocalize in mammalian sperm.

Journal Article Mol Med · January 1995 BACKGROUND: The identification of transcripts encoding putative olfactory receptors in mammalian germ cells (1) has generated the hypothesis that olfactory receptors may serve a chemosensory role in sperm chemotaxis during fertilization. We have sought to ... Link to item Cite

Ca2+-dependent interaction of recoverin with rhodopsin kinase

Journal Article Journal of Biological Chemistry · 1995 Recoverin (Rv) is a myristoylated Ca2+-binding protein present primarily in bovine photoreceptors. It represents a newly identified family of neuronal specific Ca2+-binding proteins that includes neurocalcin, hippocalcin, and guanylyl cyclase-activating pr ... Cite

Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.

Journal Article Proc Natl Acad Sci U S A · December 20, 1994 Stimulation of Gi-coupled receptors leads to the activation of mitogen-activated protein kinases (MAP kinases). In several cell types, this appears to be dependent on the activation of p21ras (Ras). Which G-protein subunit(s) (G alpha or the G beta gamma c ... Full text Open Access Link to item Cite

Determination of the G beta gamma-binding domain of phosducin. A regulatable modulator of G beta gamma signaling.

Journal Article J Biol Chem · November 25, 1994 Although a role for the beta gamma-subunits of heterotrimeric G proteins (G beta gamma) in signal transduction by several cellular systems has been established, the structural features of cellular proteins interacting with G beta gamma have yet to be fully ... Link to item Cite

Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family.

Journal Article J Biol Chem · November 11, 1994 GRK6, a 66-kDa serine/threonine protein kinase, is a recently identified member of the G protein-coupled receptor kinase (GRK) family. GRKs are involved in the phosphorylation of seven-transmembrane receptors, a process mediating desensitization of signal ... Link to item Cite

Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy.

Journal Article Proc Natl Acad Sci U S A · October 11, 1994 Transgenic mice were generated by using the alpha-myosin heavy chain promoter coupled to the coding sequence of a constitutively active mutant alpha 1B-adrenergic receptor (AR). These transgenic animals demonstrated cardiac-specific expression of this alph ... Full text Open Access Link to item Cite

Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits.

Journal Article Nature · July 14, 1994 Acetylcholine released during parasympathetic stimulation of the vagal nerve slows the heart rate through the activation of muscarinic receptors and subsequent opening of an inwardly rectifying potassium channel. The activation of these muscarinic potassiu ... Full text Link to item Cite

Inhibition of G protein-coupled receptor signaling by expression of cytoplasmic domains of the receptor.

Journal Article J Biol Chem · June 3, 1994 The third intracellular domain (3i) of G protein-coupled receptors plays a major role in the activation of G proteins. Alterations in this region of the receptor can affect receptor/G protein coupling efficiency and specificity. We recently reported (Luttr ... Link to item Cite

An approach to the study of G-protein-coupled receptor kinases: an in vitro-purified membrane assay reveals differential receptor specificity and regulation by G beta gamma subunits.

Journal Article Proc Natl Acad Sci U S A · April 26, 1994 Phosphorylation of GTP-binding-regulatory (G)-protein-coupled receptors by specific G-protein-coupled receptor kinases (GRKs) is a major mechanism responsible for agonist-mediated desensitization of signal transduction processes. However, to date, studies ... Full text Open Access Link to item Cite

Functionally active targeting domain of the beta-adrenergic receptor kinase: an inhibitor of G beta gamma-mediated stimulation of type II adenylyl cyclase.

Journal Article Proc Natl Acad Sci U S A · April 26, 1994 The beta-adrenergic receptor kinase (beta ARK) phosphorylates its membrane-associated receptor substrates, such as the beta-adrenergic receptor, triggering events leading to receptor desensitization. beta ARK activity is markedly stimulated by the isopreny ... Full text Open Access Link to item Cite

Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor.

Journal Article Science · April 22, 1994 Transgenic mice were created with cardiac-specific overexpression of the beta 2-adrenergic receptor. This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; thes ... Full text Link to item Cite

G-PROTEIN-COUPLED RECEPTOR KINASES

Journal Article FASEB JOURNAL · April 19, 1994 Link to item Cite

Binding of G protein beta gamma-subunits to pleckstrin homology domains.

Journal Article J Biol Chem · April 8, 1994 Ligand-induced activation of many receptors leads to dissociation of the alpha- and beta gamma-subunit complexes of heterotrimeric G proteins, both of which regulate a variety of effector molecules involved in cellular signaling processes. In one case, a c ... Link to item Cite

Differential desensitization and phosphorylation of three cloned and transfected alpha 2-adrenergic receptor subtypes.

Journal Article J Biol Chem · April 1, 1994 Genes encoding 3 distinct subtypes of human alpha 2-adrenergic receptor are known and are found, respectively, on chromosome 10, 4, and 2 (alpha 2-C10, alpha 2-C4, and alpha 2-C2 adrenergic receptors). All 3 receptors inhibit adenylyl cyclase via Gi protei ... Link to item Cite

A constitutively active mutant beta 2-adrenergic receptor is constitutively desensitized and phosphorylated.

Journal Article Proc Natl Acad Sci U S A · March 29, 1994 The beta 2-adrenergic receptor (beta 2AR) can be constitutively activated by mutations in the third intracellular loop. Whereas the wild-type receptor exists predominantly in an inactive conformation (R) in the absence of agonist, the mutant receptor appea ... Full text Open Access Link to item Cite

Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases.

Journal Article J Biol Chem · March 4, 1994 A novel member of the family of G protein-coupled receptor kinases (GRKs), named GRK5, has been cloned from bovine taste epithelium. The cDNA sequence predicts a 590-amino acid protein with high overall similarity to rhodopsin kinase. GRK5 mRNA is found mo ... Link to item Cite

Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor.

Journal Article Mol Pharmacol · March 1994 The beta 2-adrenergic receptor undergoes isomerization between an inactive conformation (R) and an active conformation (R*). The formation of the active conformation of the receptor molecule can be promoted by adrenergic agonists or by mutations in the thi ... Link to item Cite

Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signaling.

Journal Article J Biol Chem · February 25, 1994 The beta gamma subunits (G beta gamma) of heterotrimeric G proteins modulate the activity of several signal-transducing effector molecules including G protein-coupled receptor kinases. G beta gamma binds to the carboxyl terminus of the beta-adrenergic rece ... Link to item Cite

Localization of mRNA for three distinct alpha 1-adrenergic receptor subtypes in human tissues: implications for human alpha-adrenergic physiology.

Journal Article Mol Pharmacol · February 1994 alpha 1-Adrenergic receptors (alpha 1ARs) are virtually ubiquitous in human tissues and mediate important physiological functions as diverse as smooth muscle contraction, glycogenolysis, and myocardial inotropy. At least three alpha 1AR subtypes (alpha 1A/ ... Link to item Cite

A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration.

Journal Article J Biol Chem · January 28, 1994 An aromatic residue, tyrosine 326 in the prototypical human beta 2-adrenergic receptor, exists in a highly conserved sequence motif in virtually all members of the G protein-coupled receptor family. The potential role of this conserved aromatic amino acid ... Link to item Cite

Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases.

Journal Article J Biol Chem · January 14, 1994 The thrombin receptor, a member of the seven membrane-spanning superfamily of G-protein coupled receptors, is activated by an irreversible proteolytic mechanism, but signaling by activated thrombin receptors shuts off soon after receptor activation. This s ... Link to item Cite

Olfactory desensitization requires membrane targeting of receptor kinase mediated by beta gamma-subunits of heterotrimeric G proteins.

Journal Article J Biol Chem · January 7, 1994 Olfaction is mediated by G protein-coupled receptors. In isolated rat olfactory cilia, odorants such as citralva stimulate a burst of cAMP, which peaks in 50 ms and returns almost to base-line level within 150 ms in the continuing presence of odorant. This ... Link to item Cite

Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain.

Journal Article Brain Res Mol Brain Res · January 1994 alpha 2-Adrenergic receptors in brain are important presynaptic modulators of central noradrenergic function (autoreceptors) and postsynaptic mediators of many of the widespread effects of catecholamines and related drugs. alpha 2-Adrenergic agonists are c ... Full text Link to item Cite

Partially purified and reconstituted g-protein coupled receptors as substrates of specific receptor kinases

Journal Article Methods · January 1, 1994 Most members of the G-protein-coupled receptor (GPCR) superfamily, which includes several hundred receptors, exhibit agonist-induced desensitization. Studies with rhodopsin and β2-adrenergic receptors indicate that a key biochemical event underlying the pr ... Full text Cite

ISOPRENYLATION IN THE REGULATION OF SENSORY RECEPTORS

Journal Article JOURNAL OF NEUROCHEMISTRY · January 1, 1994 Link to item Cite

Diseased G protein-coupled receptors.

Journal Article J Clin Invest · November 1993 Full text Open Access Link to item Cite

G protein-coupled receptor kinases.

Journal Article Cell · August 13, 1993 Full text Link to item Cite

Constitutively active mutants of the alpha 2-adrenergic receptor.

Journal Article J Biol Chem · August 5, 1993 We have mutated a single residue, Thr373 [corrected], in the C-terminal portion of the third intracellular loop of the alpha 2C10-adrenergic receptor into five different amino acids. In analogy with the effect of similar mutations in the alpha 1B- and beta ... Link to item Cite

Identification, quantification, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate.

Journal Article J Urol · August 1993 The dynamic component of bladder outlet obstruction caused by benign prostatic hyperplasia (BPH) is regulated by alpha 1 adrenergic receptors (alpha 1-AR) located in the prostatic stroma. Recently two alpha 1-AR subtypes (alpha 1A, alpha 1B) have been iden ... Full text Link to item Cite

Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins.

Journal Article Trends Pharmacol Sci · August 1993 Adrenoceptors are prototypic members of the superfamily of seven transmembrane domain, G protein-coupled receptors. Study of the properties of several mutationally activated adrenoceptors is deepening understanding of the normal functioning of this ubiquit ... Full text Link to item Cite

The substance P receptor, which couples to Gq/11, is a substrate of beta-adrenergic receptor kinase 1 and 2.

Journal Article J Biol Chem · May 5, 1993 The agonist-occupied forms of several G-protein-coupled receptors that modulate the activity of adenylycyclase via Gs (e.g. beta 2-adrenergic) or Gi (e.g. alpha 2-adrenergic and cardiac muscarinic) are phosphorylated by beta-adrenergic receptor kinases (be ... Link to item Cite

Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · April 15, 1993 The physiological significance of multiple G-protein-coupled receptor subtypes, such as the beta-adrenergic receptors (beta ARs), remains obscure, since in many cases several subtypes activate the same effector and utilize the same physiological agonists. ... Full text Open Access Link to item Cite

The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase.

Journal Article J Biol Chem · April 15, 1993 The beta gamma subunits of heterotrimeric G proteins play important roles in regulating receptor-stimulated signal transduction processes. Recently appreciated among these is their role in the signaling events that lead to the phosphorylation and subsequen ... Link to item Cite

Coupling of the expressed alpha 1B-adrenergic receptor to the phospholipase C pathway in Xenopus oocytes. The role of Go.

Journal Article J Biol Chem · April 5, 1993 alpha 1B-Adrenergic receptor mRNA was injected into Xenopus oocytes, resulting in a norepinephrine-evoked Cl- current. The response was proportional to norepinephrine concentration, blocked by prazosin, and dependent on intracellular Ca2+ derived from inos ... Link to item Cite

Antagonism of catecholamine receptor signaling by expression of cytoplasmic domains of the receptors.

Journal Article Science · March 5, 1993 The actions of many hormones and neurotransmitters are mediated by the members of a superfamily of receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins). These receptors are characterized by a highly conserved topographical a ... Full text Link to item Cite

A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.

Journal Article J Biol Chem · March 5, 1993 We have replaced the C-terminal portion of the third intracellular loop of the beta 2-adrenergic receptor (residues 266-272) with the homologous region of the alpha 1B-adrenergic receptor. In a fashion analogous to the reciprocal mutations of the alpha 1B ... Link to item Cite

Characterization of alpha 2-adrenergic receptor subtype-specific antibodies.

Journal Article Mol Pharmacol · March 1993 Subtypes of alpha 2-adrenergic receptors have been defined pharmacologically in a variety of mammalian tissues. The alpha 2A, alpha 2B, alpha 2C, and most recently alpha 2D subtypes have been characterized by their affinities for selective receptor antagon ... Link to item Cite

Cloning and sequence analysis of the human beta 1-adrenergic receptor 5'-flanking promoter region.

Journal Article Biochim Biophys Acta · February 20, 1993 We present 3.1 kb of the nucleotide sequence from the 5'-flanking region of the human beta 1-adrenergic receptor gene. The first 1.0 kb upstream from the translational start site is composed of 72% G + C residues. The sequence was analyzed for the presence ... Full text Link to item Cite

Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors.

Journal Article J Biol Chem · February 15, 1993 Receptor-specific or homologous desensitization of beta 2-adrenergic receptors is thought to be effected via phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK), followed by binding of beta-arrestin. We have generated stably t ... Link to item Cite

A beta-adrenergic receptor kinase-like enzyme is involved in olfactory signal termination.

Journal Article Proc Natl Acad Sci U S A · February 15, 1993 We have previously shown that second-messenger-dependent kinases (cAMP-dependent kinase, protein kinase C) in the olfactory system are essential in terminating second-messenger signaling in response to odorants. We now document that subtype 2 of the beta-a ... Full text Open Access Link to item Cite

Beta-adrenergic receptor kinase-2 and beta-arrestin-2 as mediators of odorant-induced desensitization.

Journal Article Science · February 5, 1993 beta-Adrenergic receptor kinase (beta ARK) and beta-arrestin function in the homologous or agonist-activated desensitization of G protein-coupled receptors. The isoforms beta ARK-2 and beta-arrestin-2 are highly enriched in and localized to the dendritic k ... Full text Link to item Cite

β-adrenergic receptor sequestration: A potential mechanism of receptor resensitization

Journal Article Journal of Biological Chemistry · January 5, 1993 Continuous exposure of cells to hormonal agonists often causes a rapid waning of the stimulated response. This desensitization effect has been extensively studied in the β-adrenergic receptor system, and attributed largely to the rapid phosphorylation of t ... Cite

Beta-adrenergic receptor sequestration. A potential mechanism of receptor resensitization.

Journal Article J Biol Chem · January 5, 1993 Continuous exposure of cells to hormonal agonists often causes a rapid waning of the stimulated response. This desensitization effect has been extensively studied in the beta-adrenergic receptor system, and attributed largely to the rapid phosphorylation o ... Link to item Cite

The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain.

Journal Article J Neurosci · October 1992 The beta-adrenergic receptor kinase (beta ARK) phosphorylates the agonist-occupied beta-adrenergic receptor to promote rapid receptor uncoupling from Gs, thereby attenuating adenylyl cyclase activity. Beta ARK-mediated receptor desensitization may reflect ... Full text Open Access Link to item Cite

Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases.

Journal Article Nature · September 10, 1992 Rhodopsin kinase and beta-adrenergic receptor kinase (beta ARK) are related members of a serine/threonine kinase family that specifically initiate deactivation of G-protein-coupled receptors. After stimulus-mediated receptor activation, these cytoplasmic k ... Full text Link to item Cite

Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family.

Journal Article J Biol Chem · September 5, 1992 Homologous or agonist-specific desensitization of beta 2-adrenergic receptors (beta 2AR) is mediated by the beta-adrenergic receptor kinase (beta ARK) which specifically phosphorylates the agonist-occupied form of the receptor. However, the capacity of bet ... Link to item Cite

β-arrestin2, a novel member of the arrestin/β-arrestin gene family

Journal Article Journal of Biological Chemistry · September 5, 1992 Homologous or agonist-specific desensitization of β2-adrenergic receptors (β2AR) is mediated by the β-adrenergic receptor kinase (βARK) which specifically phosphorylates the agonist-occupied form of the receptor. However, the capacity of βARK-phosphorylate ... Cite

Overexpression of pp60c-src is associated with altered regulation of adenylyl cyclase.

Journal Article Cell Signal · September 1992 The ability of activators of the beta-adrenergic receptor to elevate intracellular cAMP levels in murine fibroblasts is enhanced upon overexpression of avian c-src [Bushman et al. (1990) Proc. natn. Acad. Sci. U.S.A. 87, 7462-7466]. To investigate the mole ... Full text Link to item Cite

Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors.

Journal Article Science · August 28, 1992 The rate and extent of the agonist-dependent phosphorylation of beta 2-adrenergic receptors and rhodopsin by beta-adrenergic receptor kinase (beta ARK) are markedly enhanced on addition of G protein beta gamma subunits. With a model peptide substrate it wa ... Full text Link to item Cite

G proteins. The subunit story thickens.

Journal Article Nature · July 30, 1992 Full text Link to item Cite

Tyrosine phosphorylation of G protein alpha subunits by pp60c-src.

Journal Article Proc Natl Acad Sci U S A · July 1, 1992 A number of lines of evidence suggest that cross-talk exists between the cellular signal transduction pathways involving tyrosine phosphorylation catalyzed by members of the pp60c-src kinase family and those mediated by guanine nucleotide regulatory protei ... Full text Open Access Link to item Cite

Pharmacological characteristics of alpha 2-adrenergic receptors: comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning.

Journal Article Mol Pharmacol · July 1992 On the basis of extensive radioligand data and more limited functional data, three pharmacological subtypes of alpha 2-adrenergic receptors have been identified. More recently, three human genes or cDNAs for alpha 2-adrenergic receptors have been identifie ... Link to item Cite

Receptor-specific desensitization with purified proteins. Kinase dependence and receptor specificity of beta-arrestin and arrestin in the beta 2-adrenergic receptor and rhodopsin systems.

Journal Article J Biol Chem · April 25, 1992 Homologous desensitization of beta-adrenergic receptors, as well as adaptation of rhodopsin, are thought to be triggered by specific phosphorylation of the receptor proteins. However, phosphorylation alone seems insufficient to inhibit receptor function, a ... Link to item Cite

CONSTITUTIVELY ACTIVE BETA-2-ADRENERGIC RECEPTOR

Journal Article CLINICAL RESEARCH · April 1, 1992 Link to item Cite

Desensitization of the isolated beta 2-adrenergic receptor by beta-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase C occurs via distinct molecular mechanisms.

Journal Article Biochemistry · March 31, 1992 Exposure of beta 2-adrenergic receptors (beta 2ARs) to agonists causes a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Phosphorylation of the beta 2AR by several distinct kinases plays an important role in this desensitization ... Full text Link to item Cite

Sites in the third intracellular loop of the alpha 2A-adrenergic receptor confer short term agonist-promoted desensitization. Evidence for a receptor kinase-mediated mechanism.

Journal Article J Biol Chem · March 5, 1992 To investigate the mechanisms of agonist-promoted desensitization of the alpha 2-adrenergic receptor (alpha 2AR), the human alpha 2AAR and a mutated form of the receptor were expressed in CHW cells. After cells were exposed to epinephrine for 30 min, the a ... Link to item Cite

Isoprenylation of a protein kinase. Requirement of farnesylation/alpha-carboxyl methylation for full enzymatic activity of rhodopsin kinase.

Journal Article J Biol Chem · January 25, 1992 The primary structure of bovine rhodopsin kinase (RK), which phosphorylates light-activated rhodopsin (Rho*), terminates with the amino acid sequence Cys558-Val-Leu-Ser561, a motif that has been shown to direct the isoprenylation and alpha-carboxyl methyla ... Link to item Cite

Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation.

Journal Article J Biol Chem · January 25, 1992 Mutations in an intracellular region of the alpha 1B-adrenergic receptor constitutively activate the receptor, resulting in G protein coupling in the absence of agonist, as evidenced by elevated levels of polyphosphoinositide hydrolysis. Remarkably, all 19 ... Link to item Cite

Discrete amino acid sequences of the alpha 1-adrenergic receptor determine the selectivity of coupling to phosphatidylinositol hydrolysis.

Journal Article J Biol Chem · January 25, 1992 We have constructed a variety of chimeric beta 2/alpha 1 adrenergic receptors (AR) in which selected portions of the third intracellular loop of the alpha (1B)AR were substituted into the corresponding regions of the beta 2AR. The mutant receptors were bot ... Link to item Cite

From ligand binding to gene expression: new insights into the regulation of G-protein-coupled receptors.

Journal Article Trends Biochem Sci · January 1992 Transmembrane signaling systems relay information from the exterior to the interior of a cell, through a series of complex protein-protein interactions and second messenger cascades. One such system consists of the G-protein-coupled receptors, which intera ... Full text Link to item Cite

Recent molecular analyses of β-adrenergic receptor phosphorylation, sequestration and down regulation

Journal Article Asia Pacific Journal of Pharmacology · January 1, 1992 Cite

G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha 1B-adrenergic receptor enhances mitogenesis and tumorigenicity.

Journal Article Proc Natl Acad Sci U S A · December 15, 1991 The alpha 1B-adrenergic receptor (alpha 1B-ADR) is a member of the G-protein-coupled family of transmembrane receptors. When transfected into Rat-1 and NIH 3T3 fibroblasts, this receptor induces focus formation in an agonist-dependent manner. Focus-derived ... Full text Open Access Link to item Cite

The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity.

Journal Article Mol Pharmacol · November 1991 We recently reported the cloning of a novel alpha 1-adrenergic receptor (AR), the alpha 1CAR. By transient and stable expression of the alpha 1CAR and the previously cloned alpha 1BAR in COS-7 and HeLa cells, respectively, we have now compared their abilit ... Link to item Cite

The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase.

Journal Article Proc Natl Acad Sci U S A · October 1, 1991 Light-dependent deactivation of rhodopsin as well as homologous desensitization of beta-adrenergic receptors involves receptor phosphorylation that is mediated by the highly specific protein kinases rhodopsin kinase (RK) and beta-adrenergic receptor kinase ... Full text Open Access Link to item Cite

Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family.

Journal Article J Biol Chem · August 15, 1991 The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. Structural features of this enzyme have been elucidated recently by the isolation of a cDNA ... Link to item Cite

Cyclic phosphorylation-dephosphorylation of rhodopsin in retina by protein kinase FA (the activator of ATP.Mg-dependent protein phosphatase).

Journal Article Biochem Biophys Res Commun · August 15, 1991 The ATP.Mg-dependent protein phosphatase activating factor (protein kinase FA) was identified to exist in bovine retina. Furthermore, rhodopsin, the visual light pigment associated with rod outer segments in retina, could be well phosphorylated by kinase F ... Full text Link to item Cite

Comparative rates of desensitization of beta-adrenergic receptors by the beta-adrenergic receptor kinase and the cyclic AMP-dependent protein kinase.

Journal Article Proc Natl Acad Sci U S A · July 15, 1991 Three separate processes may contribute to rapid beta-adrenergic receptor desensitization: functional uncoupling from the stimulatory guanine nucleotide-binding protein Gs, mediated by phosphorylation of the receptors by two distinct kinases, the specific ... Full text Link to item Cite

Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution.

Journal Article Genomics · June 1991 Five sequence-related genes encoding four adrenergic receptors and a serotonin receptor were localized to specific regions of four mouse chromosomes with respect to 11 other genetic markers. Linkage was established by the analysis of the haplotypes of 114 ... Full text Link to item Cite

Role of acidic amino acids in peptide substrates of the beta-adrenergic receptor kinase and rhodopsin kinase.

Journal Article Biochemistry · May 28, 1991 The beta-adrenergic receptor kinase (beta-ARK) phosphorylates G protein coupled receptors in an agonist-dependent manner. Since the exact sites of receptor phosphorylation by beta-ARK are poorly defined, the identification of substrate amino acids that are ... Full text Link to item Cite

cDNA cloning and chromosomal localization of the human beta-adrenergic receptor kinase.

Journal Article FEBS Lett · May 20, 1991 The beta-adrenergic receptor kinase (beta ARK) mediates agonist-dependent phosphorylation of the beta 2-adrenergic and related G protein-coupled receptors. A cDNA encoding bovine beta ARK has recently been isolated. In this work we have isolated a cDNA enc ... Full text Link to item Cite

A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation.

Journal Article Proc Natl Acad Sci U S A · April 15, 1991 Plasma membrane receptors that couple to guanine nucleotide-binding regulatory proteins (G proteins) undergo a variety of rapid (minutes) and longer term (hours) regulatory processes induced by ligands. For the beta 2-adrenergic receptor (beta 2AR), the ra ... Full text Link to item Cite

Molecular cloning and expression of the cDNA for the alpha 1A-adrenergic receptor. The gene for which is located on human chromosome 5.

Journal Article J Biol Chem · April 5, 1991 Pharmacological and molecular cloning studies have demonstrated heterogeneity of alpha 1-adrenergic receptors. We have now cloned two alpha 1-adrenergic receptors from a rat cerebral cortex cDNA library, using the hamster alpha 1B-adrenergic receptor as a ... Link to item Cite

Functional interactions of recombinant alpha 2 adrenergic receptor subtypes and G proteins in reconstituted phospholipid vesicles.

Journal Article Biochemistry · April 2, 1991 The functional interaction of the recombinant alpha 2 adrenergic receptor subtypes, alpha 2-C10 (the human platelet alpha 2 receptor, equivalent to the alpha 2 A subtype) and alpha 2-C4 (an alpha 2 receptor subtype cloned from a human kidney cDNA library), ... Full text Link to item Cite

THE ALPHA-1 ADRENERGIC-RECEPTOR - A POTENTIAL PROTOONCOGENE

Journal Article CLINICAL RESEARCH · April 1, 1991 Link to item Cite

Coupling of a mutated form of the human beta 2-adrenergic receptor to Gi and Gs. Requirement for multiple cytoplasmic domains in the coupling process.

Journal Article J Biol Chem · March 15, 1991 We constructed five genes encoding mutant human beta 2-adrenergic receptor sequence (beta 2AR) which contained 12-22 amino acid substitutions with corresponding sequence from the human alpha 2AAR in order to assess the receptor domains involved in Gs versu ... Link to item Cite

Mutations of the human beta 2-adrenergic receptor that impair coupling to Gs interfere with receptor down-regulation but not sequestration.

Journal Article Mol Pharmacol · February 1991 The integrity of coupling of the beta 2-adrenergic receptor (beta 2AR) to its guanine nucleotide-binding protein, Gs, and phosphorylation events on the receptor molecule have been proposed to be important determinants in the processes of receptor sequestra ... Link to item Cite

5-HT1A and histamine H1 receptors in HeLa cells stimulate phosphoinositide hydrolysis and phosphate uptake via distinct G protein pools.

Journal Article J Biol Chem · January 5, 1991 Regulation of phosphate uptake was studied in a HeLa cell line after transfection with DNA encoding the human 5-HT1A receptor. In these cells, 5-HT stimulates sodium-dependent phosphate uptake via protein kinase C activation. Endogenous histamine H1 recept ... Link to item Cite

Regulation of adrenergic receptor responsiveness through modulation of receptor gene expression.

Journal Article Annu Rev Physiol · 1991 Multiple mechanisms contribute to the regulation of G protein-coupled receptors and their transmembrane signaling. Post-translational modifications of the receptors, such as phosphorylation, and changes in receptor gene expression can occur in either a str ... Full text Link to item Cite

Dual coupling of the cloned 5-HT1A receptor to both adenylyl cyclase and phospholipase C is mediated via the same Gi protein.

Journal Article Cell Signal · 1991 The cloned 5-HT1A receptor, stably expressed in HeLa cells, has been shown to mediate the effects of 5-hydroxytryptamine (5-HT) to inhibit cAMP formation and to stimulate the hydrolysis of phosphatidylinositol. Both responses were found to be pertussis tox ... Full text Link to item Cite

The α1C-adrenergic receptor: Characterization of signal transduction pathways and mammalian tissue heterogeneity

Journal Article Molecular Pharmacology · 1991 We recently reported the cloning of a novel α1-adrenergic receptor (AR), the α1CAR. By transient and stable expression of the α1CAR and the previously cloned α1BAR in COS-7 and HeLa cells, respectively, we have now compared their ability to interact with m ... Cite

STRUCTURE AND MOLECULAR CHARACTERIZATION OF ALPHA-ADRENERGIC RECEPTORS

Conference ADRENOCEPTORS : STRUCTURE, MECHANISMS, FUNCTION · January 1, 1991 Link to item Cite

GENE LOCALIZATION OF THE CDNA FOR A NOVEL ALPHA(1)-ADRENERGIC RECEPTOR SUBTYPE

Journal Article CYTOGENETICS AND CELL GENETICS · January 1, 1991 Link to item Cite

The α1C-adrenergic receptor: Characterization of signal transduction pathways and mammalian tissue heterogeneity

Journal Article Molecular Pharmacology · January 1, 1991 We recently reported the cloning of a novel α1-adrenergic receptor (AR), the α1CAR. By transient and stable expression of the α1CAR and the previously cloned α1BAR in COS-7 and HeLa cells, respectively, we have now compared their ability to interact with m ... Cite

A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP.

Journal Article J Biol Chem · November 5, 1990 The rate of transcription of the beta 2-adrenergic receptor gene is increased in response to beta-adrenergic agonist stimulation of the receptor at the cell surface. This effect is mediated by stimulation of adenylyl cyclase and elevation of intracellular ... Link to item Cite

Expression of three alpha 2-adrenergic receptor subtypes in rat tissues: implications for alpha 2 receptor classification.

Journal Article Mol Pharmacol · November 1990 Based on biochemical and ligand binding studies in various tissues and species, evidence for several alpha 2-adrenergic receptor subtypes has accumulated. The current alpha 2-adrenergic receptor classification (alpha 2A, alpha 2B, alpha 2C) is based exclus ... Link to item Cite

Control of yeast mating signal transduction by a mammalian beta 2-adrenergic receptor and Gs alpha subunit.

Journal Article Science · October 5, 1990 To facilitate functional and mechanistic studies of receptor-G protein interactions, [corrected] the human beta 2-adrenergic receptor (h beta-AR) has been expressed in Saccharomyces cerevisiae. This was achieved by placing a modified h beta-AR gene under c ... Full text Link to item Cite

Turning off the signal: desensitization of beta-adrenergic receptor function.

Journal Article FASEB J · August 1990 Cellular responses to many hormones and neurotransmitters wane rapidly despite continuous exposure of cells to these stimuli. This phenomenon, termed desensitization, has been particularly well studied for the stimulation of cAMP levels by plasma membrane ... Link to item Cite

Involvement of tyrosine residues located in the carboxyl tail of the human beta 2-adrenergic receptor in agonist-induced down-regulation of the receptor.

Journal Article Proc Natl Acad Sci U S A · July 1990 Chronic exposure of various cell types to adrenergic agonists leads to a decrease in cell surface beta 2-adrenergic receptor (beta 2AR) number. Sequestration of the receptor away from the cell surface as well as a down-regulation of the total number of cel ... Full text Open Access Link to item Cite

Expansion of the alpha 2-adrenergic receptor family: cloning and characterization of a human alpha 2-adrenergic receptor subtype, the gene for which is located on chromosome 2.

Journal Article Proc Natl Acad Sci U S A · July 1990 Pharmacologic, biochemical, and genetic analyses have demonstrated the existence of multiple alpha 2-adrenergic receptor (alpha 2AR) subtypes. We have cloned a human alpha 2AR by using the polymerase chain reaction with oligonucleotide primers homologous t ... Full text Open Access Link to item Cite

The adrenergic receptors: structure/function and regulation

Journal Article European Journal of Pharmacology · July 1, 1990 Full text Cite

beta-Arrestin: a protein that regulates beta-adrenergic receptor function.

Journal Article Science · June 22, 1990 Homologous or agonist-specific desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, the beta-adrenergic receptor kinase (beta ARK). However, recent data suggest that a cofactor is required for this kinase to inhibit ... Full text Link to item Cite

Molecular cloning and expression of the cDNA for a novel alpha 1-adrenergic receptor subtype.

Journal Article J Biol Chem · May 15, 1990 A novel alpha 1-adrenergic receptor subtype has been cloned from a bovine brain cDNA library. The deduced amino acid sequence is that of a 466-residue polypeptide. The structure is similar to that of the other adrenergic receptors as well as the larger fam ... Link to item Cite

Role of phosphorylation in desensitization of the beta-adrenoceptor.

Journal Article Trends Pharmacol Sci · May 1990 Regulation of receptors allows their responses to be modified rapidly and appropriately according to the needs of the environment. Multiple mechanisms are involved in the loss of sensitivity that follows exposure to agonists. Receptor sequestration, a rapi ... Full text Link to item Cite

Alpha 2-adrenergic agonists stimulate DNA synthesis in Chinese hamster lung fibroblasts transfected with a human alpha 2-adrenergic receptor gene.

Journal Article Cell Regul · May 1990 To test the hypothesis that agents activating receptors negatively coupled to adenylyl cyclase (AC) can stimulate cell proliferation, we have expressed a human alpha 2-adrenergic receptor (alpha 2-C10) in CCL39 cells and studied the effects of alpha 2-agon ... Full text Link to item Cite

α2-Adrenergic agonists stimulate DNA synthesis in Chinese hamster lung fibroblasts transfected with a human α2-adrenergic receptor gene

Journal Article Molecular Biology of the Cell · May 1, 1990 To test the hypothesis that agents activating receptors negatively coupled to adenylyl cyclase (AC) can stimulate cell proliferation, we have expressed a human α 2 -adrenergic receptor (α 2 -C10) in CCL39 cells and studied the effects of α 2 -agonists on r ... Cite

Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function.

Journal Article Proc Natl Acad Sci U S A · April 1990 Regions of the hamster alpha 1-adrenergic receptor (alpha 1 AR) that are important in GTP-binding protein (G protein)-mediated activation of phospholipase C were determined by studying the biological functions of mutant receptors constructed by recombinant ... Full text Open Access Link to item Cite

Role of extracellular disulfide-bonded cysteines in the ligand binding function of the beta 2-adrenergic receptor.

Journal Article Biochemistry · March 6, 1990 Evidence is presented for a role of disulfide bridging in forming the ligand binding site of the beta 2-adrenergic receptor (beta AR). The presence of disulfide bonds at the ligand binding site is indicated by "competitive" inhibition by dithiothreitol (DT ... Full text Link to item Cite

Multiple pathways of rapid beta 2-adrenergic receptor desensitization. Delineation with specific inhibitors.

Journal Article J Biol Chem · February 25, 1990 Exposure of beta-adrenergic receptors (beta ARs) to agonists causes rapid desensitization of the receptor-stimulated adenylyl cyclase response. Three main mechanisms have been implicated in this process: phosphorylation of the receptors by the cAMP-depende ... Link to item Cite

Adrenergic receptors. Models for regulation of signal transduction processes.

Journal Article Hypertension · February 1990 Adrenergic receptors are prototypic models for the study of the relations between structure and function of G protein-coupled receptors. Each receptor is encoded by a distinct gene. These receptors are integral membrane proteins with several striking struc ... Full text Open Access Link to item Cite

Chromosomal organization of adrenergic receptor genes.

Journal Article Proc Natl Acad Sci U S A · February 1990 The adrenergic receptors (ARs) (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmi ... Full text Open Access Link to item Cite

REGULATION OF G-PROTEIN COUPLED RECEPTORS

Journal Article BIOPHYSICAL JOURNAL · February 1, 1990 Link to item Cite

A mutation of the beta 2-adrenergic receptor impairs agonist activation of adenylyl cyclase without affecting high affinity agonist binding. Distinct molecular determinants of the receptor are involved in physical coupling to and functional activation of Gs.

Journal Article J Biol Chem · January 25, 1990 Activation of guanyl nucleotide regulatory proteins (G proteins) by hormones and neurotransmitters appears to require the formation of high affinity agonist-receptor-G protein ternary complexes. In the case of the beta 2-adrenergic receptor, multiple regio ... Link to item Cite

Multiple second messenger pathways of alpha-adrenergic receptor subtypes expressed in eukaryotic cells.

Journal Article J Biol Chem · January 5, 1990 The alpha-adrenergic receptors mediate the effects of epinephrine and norepinephrine on cellular signaling systems via guanine nucleotide binding regulatory proteins (G-proteins). Three alpha-adrenergic receptor subtypes have been cloned: the alpha 1, the ... Link to item Cite

Adrenergic receptors.

Journal Article Harvey Lect · 1990 Link to item Cite

Synthetic peptides of the hamster beta 2-adrenoceptor as substrates and inhibitors of the beta-adrenoceptor kinase.

Journal Article Br J Clin Pharmacol · 1990 1. The beta-adrenoceptor is one of a number of G protein-coupled receptors which have been proposed to contain seven transmembrane alpha-helices. The function of this receptor appears to be regulated by phosphorylation by a specific enzyme, the beta-adreno ... Full text Link to item Cite

The adrenergic receptors.

Journal Article Adv Second Messenger Phosphoprotein Res · 1990 Link to item Cite

Two kinases mediate agonist-dependent phosphorylation and desensitization of the beta 2-adrenergic receptor.

Journal Article Symp Soc Exp Biol · 1990 Binding of the catecholamine agonists epinephrine and norepinephrine to the beta-adrenergic receptor (BAR) rapidly activates adenylate cyclase via the stimulatory guanine nucleotide regulatory protein Gs, and results in rises in cellular levels of cAMP. Ho ... Link to item Cite

α2-Adrenergic agonists stimulate DNA synthesis in Chinese hamster lung fibroblasts transfected with a human α2-adrenergic receptor gene

Journal Article Molecular Biology of the Cell · 1990 To test the hypothesis that agents activating receptors negatively coupled to adenylyl cyclase (AC) can stimulate cell proliferation, we have expressed a human α2-adrenergic receptor (α2-C10) in CCL39 cells and studied the effects of α2-agonists on reiniti ... Cite

The human 5-HT1A receptor expressed in HeLa cells stimulates sodium-dependent phosphate uptake via protein kinase C.

Journal Article J Biol Chem · December 25, 1989 Regulation of phosphate uptake was studied in HeLa cell lines after transfection with DNA encoding the human 5-HT1A receptor. Phosphate uptake was saturable and greater than 90% sodium-dependent, with Vmax approximately 30-35% without changing Km. Treatmen ... Link to item Cite

Substitution of an extracellular cysteine in the beta 2-adrenergic receptor enhances agonist-promoted phosphorylation and receptor desensitization.

Journal Article Biochem Biophys Res Commun · November 30, 1989 We constructed and expressed in a permanent cell line a beta 2-adrenergic receptor with a valine substitution for cysteine 184 of the second putative extracellular loop. The mutant receptor was partially uncoupled from adenylyl cyclase with impaired abilit ... Full text Link to item Cite

Beta-adrenergic receptor kinase: primary structure delineates a multigene family.

Journal Article Science · October 13, 1989 The beta-adrenergic receptor kinase (beta-ARK), which specifically phosphorylates only the agonist-occupied form of the beta-adrenergic and closely related receptors, appears to be important in mediating rapid agonist-specific (homologous) desensitization. ... Full text Link to item Cite

Two distinct pathways for cAMP-mediated down-regulation of the beta 2-adrenergic receptor. Phosphorylation of the receptor and regulation of its mRNA level.

Journal Article J Biol Chem · October 5, 1989 We have studied cyclic AMP-mediated regulation of the beta 2-adrenergic receptor (beta 2AR). The effects of cAMP were assessed in Chinese hamster fibroblast (CHW) cells expressing either the wild type human beta 2AR receptor (CH-beta 2) or mutated forms of ... Link to item Cite

Altered patterns of agonist-stimulated cAMP accumulation in cells expressing mutant beta 2-adrenergic receptors lacking phosphorylation sites.

Journal Article Mol Pharmacol · October 1989 As with many other receptor-effector systems, the responsiveness of the beta-adrenergic receptor (beta AR)/adenylyl cyclase system undergoes desensitization upon agonist exposure. Phosphorylations of the receptor by the cAMP-dependent protein kinase (prote ... Link to item Cite

The new biology of drug receptors.

Journal Article Biochem Pharmacol · September 15, 1989 Full text Link to item Cite

Effector coupling mechanisms of the cloned 5-HT1A receptor.

Journal Article J Biol Chem · September 5, 1989 The signal transduction pathways of the cloned human 5-HT1A receptor have been examined in two mammalian cell lines transiently (COS-7) or permanently (HeLa) expressing this receptor gene. In both systems, 5-hydroxytryptamine (5-HT, serotonin) mediated a m ... Link to item Cite

Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization.

Journal Article J Biol Chem · July 25, 1989 Continuous exposure of cells to neurotransmitter or hormone agonists often results in a rapid desensitization of the cellular response. For example, pretreatment of Chinese hamster fibroblasts (CHW cells) expressing beta 2-adrenergic receptors (beta 2AR) w ... Link to item Cite

cAMP stimulates transcription of the beta 2-adrenergic receptor gene in response to short-term agonist exposure.

Journal Article Proc Natl Acad Sci U S A · July 1989 In addition to conveying cellular responses to an effector molecule, receptors are often themselves regulated by their effectors. We have demonstrated that epinephrine modulates both the rate of transcription of the beta 2-adrenergic receptor (beta 2AR) ge ... Full text Open Access Link to item Cite

Identification of the ligand-binding subunit of the human 5-hydroxytryptamine1A receptor with N-(p-azido-m-[125I] iodophenethyl)spiperone, a high affinity radioiodinated photoaffinity probe.

Journal Article Mol Pharmacol · July 1989 The ligand-binding subunit of the human 5-hydroxytryptamine1A (5-HT1A) receptor transiently expressed in COS-7 cells and of the native human 5-HT1A receptor derived from hippocampus and frontal cortex were identified by photoaffinity labeling with N-(p-azi ... Link to item Cite

Phosphorylation of chick heart muscarinic cholinergic receptors by the beta-adrenergic receptor kinase.

Journal Article Biochemistry · May 30, 1989 Previous studies have demonstrated that muscarinic cholinergic receptors (mAChR) become markedly phosphorylated when intact cardiac cells are stimulated with a muscarinic agonist. This process appears to be related to the process of receptor desensitizatio ... Full text Link to item Cite

Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor.

Journal Article J Biol Chem · May 5, 1989 We report that a cysteine residue in the human beta 2-adrenergic receptor (beta 2AR) is covalently modified by thioesterification with palmitic acid. By site-directed mutagenesis of the receptor, we have identified Cys341 in the carboxyl tail of the protei ... Link to item Cite

Localization of the fourth membrane spanning domain as a ligand binding site in the human platelet alpha 2-adrenergic receptor.

Journal Article Biochemistry · May 2, 1989 The human platelet alpha 2-adrenergic receptor is an integral membrane protein which binds epinephrine. The gene for this receptor has been cloned, and the primary structure is thus known [Kobilka et al. (1987) Science 238, 650-656]. A model of its seconda ... Full text Link to item Cite

Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning.

Journal Article Clin Chem · May 1989 The beta 1- and beta 2-adrenergic receptor subtypes are biochemically and functionally similar, because both receptors mediate the catecholamine-dependent activation of adenylate cyclase through the GTP-binding protein, Gs. Pharmacologically, the two recep ... Link to item Cite

Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.

Journal Article Proc Natl Acad Sci U S A · May 1989 Homologous (agonist-specific) desensitization of beta-adrenergic receptors (beta ARs) is accompanied by and appears to require phosphorylation of the receptors. We have recently described a novel protein kinase, beta AR kinase, which phosphorylates beta AR ... Full text Open Access Link to item Cite

Inhibition of the beta-adrenergic receptor kinase by polyanions.

Journal Article J Biol Chem · April 25, 1989 The beta-adrenergic receptor kinase, which specifically phosphorylates the agonist-occupied beta-adrenergic receptor, is strongly inhibited by polyanions. Heparin and dextran sulfate inhibit the enzyme with an IC50 of approximately 0.15 microM. De-N-sulfat ... Link to item Cite

EFFECTOR COUPLING MECHANISMS OF THE SEROTONIN (5HT1A) RECEPTOR

Journal Article CLINICAL RESEARCH · April 1, 1989 Link to item Cite

Structure of the adrenergic and related receptors.

Journal Article Annu Rev Neurosci · 1989 The isolation and sequencing of a number of G protein-coupled receptors has now provided extensive primary structure information for this family of homologous proteins. The diverse nature of these receptors suggests that the family of proteins may grow to ... Full text Link to item Cite

Adrenergic receptor homologies in vertebrate and invertebrate species examined by DNA hybridization.

Journal Article Life Sci · 1989 The deduced protein sequences of the mammalian adrenergic receptors (ARs) suggest that these proteins have evolved by several ancient gene duplication events. To investigate in what species these events may have occurred DNA fragments encoding the family o ... Full text Link to item Cite

The mammalian beta-adrenergic receptors.

Journal Article Oxf Surv Eukaryot Genes · 1989 Link to item Cite

Genetic regulation of beta-adrenergic receptors.

Journal Article Annu Rev Physiol · 1989 Several members of the family of receptors coupled to G proteins have been cloned in recent years. From the primary sequence information furnished by these clones, a characteristic seven-membrane spanning topography has emerged as the prototype for this cl ... Full text Link to item Cite

THE GENOMIC CLONE G-21 ENCODES THE HUMAN 5-HT1A RECEPTOR

Journal Article KIDNEY INTERNATIONAL · January 1, 1989 Link to item Cite

Structural basis of beta-adrenergic receptor subtype specificity studied with chimeric beta 1/beta 2-adrenergic receptors.

Journal Article Proc Natl Acad Sci U S A · December 1988 The beta 1- and beta 2-adrenergic receptors are two structurally related, but pharmacologically distinguishable, receptor subtypes, both of which activate adenylyl cyclase in a catecholamine-dependent manner through the guanine nucleotide-binding regulator ... Full text Open Access Link to item Cite

Site-directed mutagenesis of the cytoplasmic domains of the human beta 2-adrenergic receptor. Localization of regions involved in G protein-receptor coupling.

Journal Article J Biol Chem · November 5, 1988 Numerous plasma membrane-bound receptors are coupled to various effectors via a family of guanine nucleotide regulatory proteins (G proteins). Amino acid sequences of these receptors, deduced from cDNA and genomic clones, indicate the presence of seven tra ... Link to item Cite

Molecular cloning and expression of the cDNA for the hamster alpha 1-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · October 1988 The cDNA for the Syrian hamster alpha 1-adrenergic receptor has been cloned with oligonucleotides corresponding to the partial amino acid sequence of the receptor protein purified from DDT1MF-2 smooth muscle cells. The deduced amino acid sequence encodes a ... Full text Open Access Link to item Cite

The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT1A receptor.

Journal Article Nature · September 22, 1988 The recent cloning of the complementary DNAs and/or genes for several receptors linked to guanine nucleotide regulatory proteins including the adrenergic receptors (alpha 1, alpha 2A, alpha 2B, beta 1, beta 2), several subtypes of the muscarinic cholinergi ... Full text Link to item Cite

Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype.

Journal Article Proc Natl Acad Sci U S A · September 1988 An alpha 2-adrenergic receptor subtype has been cloned from a human kidney cDNA library using the gene for the human platelet alpha 2-adrenergic receptor as a probe. The deduced amino acid sequence resembles the human platelet alpha 2-adrenergic receptor a ... Full text Open Access Link to item Cite

Beta-adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids.

Journal Article J Biol Chem · July 5, 1988 Steroid hormones modulate adrenergic receptor responsiveness and receptor number. To investigate the regulation of the beta 2-adrenergic receptor gene by glucocorticoids we examined the effects of the synthetic glucocorticoid agonist triamcinolone acetonid ... Link to item Cite

Dephosphorylation of the beta 2-adrenergic receptor and rhodopsin by latent phosphatase 2.

Journal Article J Biol Chem · June 25, 1988 Recent evidence suggests that the function of receptors coupled to guanine nucleotide regulatory proteins may be controlled by highly specific protein kinases, e.g. rhodopsin kinase and the beta-adrenergic receptor kinase. In order to investigate the natur ... Link to item Cite

Regulation of the beta 2-adrenergic receptor and its mRNA in the rat ventral prostate by testosterone.

Journal Article FEBS Lett · June 6, 1988 To investigate the regulation of beta 2AR expression in rat ventral prostate the effects of castration and testosterone replacement on the beta 2AR were studied by ligand binding and Northern blot analysis. Orchidectomy depressed beta 2AR number by 50% wit ... Full text Link to item Cite

Chimeric alpha 2-,beta 2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity.

Journal Article Science · June 3, 1988 The alpha 2 and beta 2 adrenergic receptors, both of which are activated by epinephrine, but which can be differentiated by selective drugs, have opposite effects (inhibitory and stimulatory) on the adenylyl cyclase system. The two receptors are homologous ... Full text Link to item Cite

Removal of phosphorylation sites from the beta 2-adrenergic receptor delays onset of agonist-promoted desensitization.

Journal Article Nature · May 26, 1988 Eukaryotic cells have evolved a variety of mechanisms for dampening their responsiveness to hormonal stimulation in the face of sustained activation. The mechanisms for such processes, collectively referred to as desensitization, often involve alterations ... Full text Link to item Cite

Identification and sequence of a binding site peptide of the beta 2-adrenergic receptor.

Journal Article Biochemistry · March 22, 1988 p-(Bromoacetamido)benzyl-1-[125I]iodocarazolol (125I-pBABC) is a potent derivative of the beta-adrenergic receptor antagonist p-aminobenzylcarazolol. Treatment of the receptor with 125I-pBABC results in efficient covalent incorporation of the ligand into t ... Full text Link to item Cite

beta-Adrenergic receptor kinase. Activity of partial agonists for stimulation of adenylate cyclase correlates with ability to promote receptor phosphorylation.

Journal Article J Biol Chem · March 15, 1988 The beta-adrenergic receptor (beta AR) kinase is a recently discovered enzyme which specifically phosphorylates the agonist-occupied form of the beta-adrenergic receptor. We have utilized the agonist-dependent nature of this phosphorylation reaction to cha ... Link to item Cite

Expression of a human cDNA encoding the beta 2-adrenergic receptor in Chinese hamster fibroblasts (CHW): functionality and regulation of the expressed receptors.

Journal Article Mol Pharmacol · February 1988 A human beta-adrenergic receptor cDNA was transfected and expressed in transformed Chinese hamster fibroblasts (CHW). The expressed receptor exhibited a typical beta 2-adrenergic selectivity for agonists and antagonists as assessed by radioligand binding a ... Link to item Cite

The beta-adrenergic receptor kinase: role in homologous desensitization in S49 lymphoma cells.

Journal Article Adv Exp Med Biol · 1988 Phosphorylation of the beta-adrenergic receptor (beta AR) is closely associated with homologous desensitization of the beta-adrenergic receptor-coupled adenylate cyclase system. Homologous desensitization and receptor phosphorylation also occur in cell mut ... Full text Link to item Cite

Cloning of the cDNA and genes for the hamster and human beta 2-adrenergic receptors.

Journal Article J Recept Res · 1988 The adenylate cyclase-stimulatory beta 2-adrenergic receptor has been purified to apparent homogeneity from hamster lung. Partial amino acid sequence obtained from isolated CNBr peptides was used to clone the gene and cDNA for this receptor. The predicted ... Full text Link to item Cite

Adrenergic receptors.

Journal Article Adv Second Messenger Phosphoprotein Res · 1988 Link to item Cite

Molecular biology of adrenergic receptors.

Journal Article Cold Spring Harb Symp Quant Biol · 1988 Full text Link to item Cite

β-Adrenergic receptor kinase. Activity of partial agonists for stimulation of adenylate cyclase correlates with ability to promote receptor phosphorylation

Journal Article Journal of Biological Chemistry · January 1, 1988 The β-adrenergic receptor (βAR) kinase is a recently discovered enzyme which specifically phosphorylates the agonist-occupied form of the β-adrenergic receptor. We have utilized the agonist-dependent nature of this phosphorylation reaction to characterize ... Cite

β2-Adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids

Journal Article Journal of Biological Chemistry · 1988 Steroid hormones modulate adrenergic receptor responsiveness and receptor number. To investigate the regulation of the β2-adrenergic receptor gene by glucocorticoids we examined the effects of the synthetic glucocorticoid agonist triamcinolone acetonide on ... Cite

Biochemical mechanisms of β-adrenergic receptor regulation

Journal Article ISI Atlas of Science: Pharmacology · January 1, 1988 β-Adrenergic receptors for catecholamines, which stimulate adenylate cyclase, are prototypes of a large gene family of receptors which interact with guanine nucleotide regulatory proteins. The function of such receptors is dynamically regulated so that sti ... Cite

β2-Adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids

Journal Article Journal of Biological Chemistry · January 1, 1988 Steroid hormones modulate adrenergic receptor responsiveness and receptor number. To investigate the regulation of the β2-adrenergic receptor gene by glucocorticoids we examined the effects of the synthetic glucocorticoid agonist triamcinolone acetonide on ... Cite

Agonist-dependent phosphorylation of the alpha 2-adrenergic receptor by the beta-adrenergic receptor kinase.

Journal Article J Biol Chem · December 25, 1987 Desensitization of the beta-adrenergic receptor, a receptor which is coupled to the stimulation of adenylate cyclase, may be regulated via phosphorylation by a unique protein kinase. This recently discovered enzyme, known as the beta-adrenergic receptor ki ... Link to item Cite

Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein).

Journal Article Proc Natl Acad Sci U S A · December 1987 The beta-adrenergic receptor kinase is an enzyme, possibly analogous to rhodopsin kinase, that multiply phosphorylates the beta-adrenergic receptor only when it is occupied by stimulatory agonists. Since this kinase may play an important role in mediating ... Full text Open Access Link to item Cite

Functional activity and regulation of human beta 2-adrenergic receptors expressed in Xenopus oocytes.

Journal Article J Biol Chem · November 15, 1987 The recently cloned human beta-adrenergic cDNA and several mutated forms have been expressed in Xenopus laevis oocytes by injection of RNA made from the cDNA under the control of the bacteriophage SP6 promoter. The cDNA and gene of the beta 2-adrenergic re ... Link to item Cite

Cloning of the cDNA for the human beta 1-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · November 1987 Screening of a human placenta lambda gt11 library has led to the isolation of the cDNA for the human beta 1-adrenergic receptor (beta 1AR). Used as the probe was the human genomic clone termed G-21. This clone, which contains an intronless gene for a putat ... Full text Open Access Link to item Cite

Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor.

Journal Article Science · October 30, 1987 The gene for the human platelet alpha 2-adrenergic receptor has been cloned with oligonucleotides corresponding to the partial amino acid sequence of the purified receptor. The identity of this gene has been confirmed by the binding of alpha 2-adrenergic l ... Full text Link to item Cite

The multiple membrane spanning topography of the beta 2-adrenergic receptor. Localization of the sites of binding, glycosylation, and regulatory phosphorylation by limited proteolysis.

Journal Article J Biol Chem · October 15, 1987 The beta 2-adrenergic receptor (beta-AR) is an integral membrane glycoprotein of apparent Mr approximately equal to 64,000. The amino acid sequence deduced from the beta-AR gene reveals homology with the visual pigment rhodopsin of retinal rod outer segmen ... Link to item Cite

Phosphorylation of the beta-adrenergic receptor in intact cells: relationship to heterologous and homologous mechanisms of adenylate cyclase desensitization.

Journal Article Arch Biochem Biophys · October 1987 We have recently shown that both heterologous and homologous forms of adenylate cyclase desensitization involve phosphorylation of beta-adrenergic receptors. In order to compare these two reactions, we wished to identify a single cell system in which both ... Full text Link to item Cite

THE ADRENERGIC-RECEPTORS

Journal Article CIRCULATION · October 1, 1987 Link to item Cite

An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins.

Journal Article Nature · September 3, 1987 Plasma membrane receptors for hormones, drugs, neurotransmitters and sensory stimuli are coupled to guanine nucleotide regulatory proteins. Recent cloning of the genes and/or cDNAs for several of these receptors including the visual pigment rhodopsin, the ... Full text Link to item Cite

Purification and characterization of the beta-adrenergic receptor kinase.

Journal Article J Biol Chem · July 5, 1987 The beta-adrenergic receptor kinase (beta-ARK) is a recently discovered enzyme which specifically phosphorylates the agonist-occupied form of the beta-adrenergic receptor (beta-AR) as well as the light-bleached form of rhodopsin. beta-ARK is present in a w ... Link to item Cite

Delineation of the intronless nature of the genes for the human and hamster beta 2-adrenergic receptor and their putative promoter regions.

Journal Article J Biol Chem · May 25, 1987 The beta 2-adrenergic receptor is the first adenylate cyclase-coupled receptor to be cloned. We provide here a detailed characterization of its complete gene in both the human and hamster which reveals several unusual and provocative features. The genes ar ... Link to item Cite

Somatostatin induces translocation of the beta-adrenergic receptor kinase and desensitizes somatostatin receptors in S49 lymphoma cells.

Journal Article J Biol Chem · May 15, 1987 The beta-adrenergic receptor kinase is a cytosolic enzyme that specifically phosphorylates the agonist-occupied form of the beta-adrenergic receptor (beta AR). Beta AR kinase appears to be translocated from the cytosol to the plasma membrane when kin- S49 ... Link to item Cite

Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation.

Journal Article Nature · May 7, 1987 Receptor-mediated activation of both adenylate cyclase and phosphatidylinositide hydrolysis systems occurs through guanine nucleotide regulatory proteins and ultimately leads to specific activation of either cyclic AMP-dependent protein kinase A or Ca2+/ph ... Full text Link to item Cite

TOPOLOGY OF THE BETA-ADRENERGIC-RECEPTOR

Journal Article FEDERATION PROCEEDINGS · May 1, 1987 Link to item Cite

Regulation of transmembrane signaling by receptor phosphorylation.

Journal Article Cell · March 27, 1987 At least two major effects of receptor phosphorylation have been identified--regulation of receptor function, and regulation of receptor distribution. In many cases where phosphorylation directly alters the functions of receptors, this appears to be in a n ... Full text Link to item Cite

Functional differences in the beta gamma complexes of transducin and the inhibitory guanine nucleotide regulatory protein.

Journal Article Biochemistry · March 10, 1987 We have examined the mechanism of inhibition of adenylate cyclase using the purified alpha and beta gamma subunits of bovine brain inhibitory guanine nucleotide regulatory protein (Ni) (i.e., alpha i and beta gamma N) and bovine retinal transducin (alpha T ... Full text Link to item Cite

Regulation of adrenergic receptor function by phosphorylation. I. Agonist-promoted desensitization and phosphorylation of alpha 1-adrenergic receptors coupled to inositol phospholipid metabolism in DDT1 MF-2 smooth muscle cells.

Journal Article J Biol Chem · March 5, 1987 Continuous exposure of DDT1 MF-2 smooth muscle cells to 10-100 microM norepinephrine results in a dramatic attenuation of the ability of norepinephrine to stimulate inositol phospholipid hydrolysis via alpha 1-adrenergic receptors (alpha 1-AR). In addition ... Link to item Cite

Regulation of adrenergic receptor function by phosphorylation. II. Effects of agonist occupancy on phosphorylation of alpha 1- and beta 2-adrenergic receptors by protein kinase C and the cyclic AMP-dependent protein kinase.

Journal Article J Biol Chem · March 5, 1987 The present study was undertaken to determine the ability of protein kinase C and protein kinase A to directly phosphorylate the purified alpha 1- and beta 2-adrenergic receptors (AR). Both the catalytic subunit of protein kinase A and the protein kinase C ... Link to item Cite

Molecular mechanisms of beta-adrenergic receptor desensitization.

Journal Article Adv Exp Med Biol · 1987 Multiple mechanisms seem to be involved in regulating the responsiveness of hormone receptor-coupled adenylate cyclase systems. These mechanisms at least involve the receptors and nucleotide regulatory proteins. With the recent development of methods for p ... Full text Link to item Cite

The mammalian beta-adrenergic receptor: structural and functional characterization of the carbohydrate moiety.

Journal Article J Recept Res · 1987 Mammalian beta-adrenergic receptors are glycoproteins consisting of a single polypeptide chain of Mr approximately 64,000. Treatment of purified [125I]-labeled hamster lung beta-adrenergic receptor with alpha-mannosidase reveals two discrete populations of ... Full text Link to item Cite

cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor.

Journal Article Proc Natl Acad Sci U S A · January 1987 We have isolated and sequenced a cDNA encoding the human beta 2-adrenergic receptor. The deduced amino acid sequence (413 residues) is that of a protein containing seven clusters of hydrophobic amino acids suggestive of membrane-spanning domains. While the ... Full text Open Access Link to item Cite

Functional activity and regulation of human β2-adrenergic receptors expressed in Xenopus oocytes

Journal Article Journal of Biological Chemistry · January 1, 1987 The recently cloned human β-adrenergic cDNA and several mutated forms have been expressed in Xenopus laevis oocytes by injection of RNA made from the cDNA under the control of the bacteriophage SP6 promoter. The cDNA and gene of the β2-adrenergic receptor ... Cite

Beta-adrenergic receptor-coupled adenylate cyclase. Biochemical mechanisms of regulation.

Journal Article Mol Neurobiol · 1987 Beta-adrenergic receptor-coupled adenylate cyclase is regulated by both amplification and desensitization processes. Desensitization of adenylate cyclase is divided into two major categories. Homologous desensitization is initiated by phosphorylation of th ... Full text Link to item Cite

Regulation Of Receptor Function

Journal Article Enzymes · January 1, 1987 This chapter summarizes the phosphorylation of several important plasma membrane receptors: the β-adrenergic receptor coupled to adenylate cyclase; rhodopsin, the archetypal “light” receptor of the rod outer segment; the nicotinic cholinergic receptor; the ... Full text Cite

SUBUNIT INTERACTIONS - DISCUSSION

Journal Article KIDNEY INTERNATIONAL · 1987 Cite

MOLECULAR AND REGULATORY PROPERTIES OF ADENYLATE-CYCLASE COUPLED ADRENERGIC-RECEPTORS

Journal Article JOURNAL OF CELLULAR BIOCHEMISTRY · January 1, 1987 Link to item Cite

Phosphorylation/dephosphorylation of the beta-adrenergic receptor regulates its functional coupling to adenylate cyclase and subcellular distribution.

Journal Article Proc Natl Acad Sci U S A · December 1986 Prolonged exposure of cells or tissues to drugs or hormones such as catecholamines leads to a state of refractoriness to further stimulation by that agent, known as homologous desensitization. In the case of the beta-adrenergic receptor coupled to adenylat ... Full text Open Access Link to item Cite

Chemical modification of alpha 2-adrenoceptors. Possible role for tyrosine in the ligand binding site.

Journal Article Biochem Pharmacol · November 15, 1986 Tetranitromethane (TNM) is a reagent which reacts with the tyrosine and cysteine residues of proteins. Chemical modification of partially purified human platelet alpha 2-adrenoceptors with TNM resulted in an irreversible loss of binding activity. Typically ... Full text Link to item Cite

Ciba-Geigy award for outstanding research. Regulation of adrenergic receptor function by phosphorylation.

Journal Article J Mol Cell Cardiol · September 1986 The various subtypes of adrenergic receptors represent distinct structural entities which are coupled in different ways to two major transmembrane signalling systems, the adenylate cyclase and phosphatidyl-inositol pathways. Recent evidence suggests that t ... Full text Link to item Cite

Beta-agonist- and prostaglandin E1-induced translocation of the beta-adrenergic receptor kinase: evidence that the kinase may act on multiple adenylate cyclase-coupled receptors.

Journal Article Proc Natl Acad Sci U S A · September 1986 beta-Adrenergic receptor kinase (beta-AR kinase) is a cytosolic enzyme that phosphorylates the beta-adrenergic receptor only when it is occupied by an agonist [Benovic, J. Strasser, R. H., Caron, M. G. & Lefkowitz, R. J. (1986) Proc. Natl. Acad. Sci. USA 8 ... Full text Open Access Link to item Cite

Mechanism of guanine nucleotide regulatory protein-mediated inhibition of adenylate cyclase. Studies with isolated subunits of transducin in a reconstituted system.

Journal Article J Biol Chem · July 15, 1986 The retinal nucleotide regulatory protein, transducin, can substitute for the inhibitory guanine nucleotide-binding regulatory protein (Ni) in inhibiting adenylate cyclase activity in phospholipid vesicle systems. In the present work we have assessed the r ... Link to item Cite

Light-dependent phosphorylation of rhodopsin by beta-adrenergic receptor kinase.

Journal Article Nature · June 26, 1986 The structural components involved in transduction of extracellular signals as diverse as a photon of light impinging on the retina or a hormone molecule impinging on a cell have been highly conserved. These components include a recognition unit or recepto ... Full text Link to item Cite

Mammalian alpha 1-adrenergic receptor. Purification and characterization of the native receptor ligand binding subunit.

Journal Article J Biol Chem · June 15, 1986 alpha 1-Adrenergic receptors from a cultured smooth muscle cell line (DDT1 MF-2) have been solubilized with digitonin and purified to apparent homogeneity by sequential chromatography on a biospecific affinity support (Sepharose-A55453 (4-amino-6,7-dimetho ... Link to item Cite

Photoaffinity labeling of human platelet and rabbit kidney alpha 2-adrenoceptors with [3H]SKF 102229.

Journal Article Biochem Biophys Res Commun · June 13, 1986 A newly developed alpha 2-adrenergic photoaffinity ligand, 3-methyl-6-chloro-9-azido-1H-2,3,4,5-tetrahydro-3-benzazepine (SKF 102229), has been radiolabeled with tritium to a specific activity of approximately 80 Ci/mmol. Using membranes prepared from huma ... Full text Link to item Cite

Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor.

Journal Article Proc Natl Acad Sci U S A · May 1986 Agonist-promoted desensitization of adenylate cyclase is intimately associated with phosphorylation of the beta-adrenergic receptor in mammalian, avian, and amphibian cells. However, the nature of the protein kinase(s) involved in receptor phosphorylation ... Full text Open Access Link to item Cite

Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin.

Journal Article Nature · May 1, 1986 The adenylate cyclase system, which consists of a catalytic moiety and regulatory guanine nucleotide-binding proteins, provides the effector mechanism for the intracellular actions of many hormones and drugs. The tissue specificity of the system is determi ... Full text Link to item Cite

Identification of the subunit structure of rat pineal adrenergic receptors by photoaffinity labeling.

Journal Article J Neurochem · April 1986 The adrenergic receptors of rat pineal gland were investigated using radiolabeled ligand binding and photoaffinity labeling techniques. 125I-2-[beta-(4-hydroxyphenyl)ethylaminomethyl]tetralone (125I-HEAT) and 125I-cyanopindolol (125I-CYP) labeled specific ... Full text Link to item Cite

A novel catecholamine-activated adenosine cyclic 3',5'-phosphate independent pathway for beta-adrenergic receptor phosphorylation in wild-type and mutant S49 lymphoma cells: mechanism of homologous desensitization of adenylate cyclase.

Journal Article Biochemistry · March 25, 1986 Virtually all known biological actions stimulated by beta-adrenergic and other adenylate cyclase coupled receptors are mediated by cAMP-dependent protein kinase. Nonetheless, "homologous" or beta-adrenergic agonist-specific desensitization does not require ... Full text Link to item Cite

Purification and characterization of the human platelet alpha 2-adrenergic receptor.

Journal Article J Biol Chem · March 15, 1986 Human platelet alpha 2-adrenergic receptors have been purified approximately 80,000-fold to apparent homogeneity by a five-step chromatographic procedure. The overall yield starting from the membranes is approximately 2%. Sodium dodecyl sulfate-polyacrylam ... Link to item Cite

Functional reconstitution of the alpha 2-adrenergic receptor with guanine nucleotide regulatory proteins in phospholipid vesicles.

Journal Article J Biol Chem · March 15, 1986 We describe the successful reconstitution of functional interactions between an inhibitory adenylate cyclase-coupled receptor and various nucleotide-binding regulatory proteins in phospholipid vesicles. The receptor is the alpha 2-adrenergic receptor (alph ... Link to item Cite

Regulation of adrenergic receptor function by phosphorylation.

Journal Article Curr Top Cell Regul · 1986 Mounting evidence suggests that the physiological function of the various subtypes of adrenergic receptors is controlled by phosphorylation/dephosphorylation reactions. It seems intuitively unlikely that this phenomenon will be limited simply to the adrene ... Full text Link to item Cite

β-Adrenergic receptors and rhodopsin: shedding new light on an old subject

Journal Article Trends in Pharmacological Sciences · January 1, 1986 Among the best studied systems for transmembrane signalling in plasma membranes are the β-adrenergic receptor-adenylate cyclase system which responds to catecholamines and the visual transduction system of the rod outer segment which responds to light. Rob ... Full text Cite

Phorbol diester treatment promotes enhanced adenylate cyclase activity in frog erythrocytes.

Journal Article Arch Biochem Biophys · January 1986 Incubation of intact frog erythrocytes with 12-O-tetradecanoyl phorbol-13-acetate (TPA), a tumor-promoting phorbol diester which activates protein kinase C, results in an approximate two- to threefold increase in subsequently tested beta-adrenergic agonist ... Full text Link to item Cite

Phorbol ester effects on alpha 1-adrenoceptor binding and phosphatidylinositol metabolism in cultured vascular smooth muscle cells.

Journal Article Life Sci · December 23, 1985 Tumor promoting phorbol esters stimulate Ca++ phospholipid-dependent protein kinase C. It has been suggested that this enzyme regulates the functional properties of different cell membrane receptors. In this study we investigated the effect of phorbol este ... Full text Link to item Cite

A role for Ni in the hormonal stimulation of adenylate cyclase.

Journal Article Nature · November 21, 1985 The best understood system for transduction of extracellular messages into intracellular signals is the hormone receptor-coupled adenylate cyclase. In such systems receptors are functionally coupled to the enzyme by two special proteins, termed the stimula ... Full text Link to item Cite

Arylazide photoaffinity probe for alpha 2-adrenoceptors.

Journal Article Biochem Pharmacol · October 15, 1985 An arylazide photoaffinity probe for alpha 2-adrenoceptors has been developed and characterized. The compound, 3-methyl-6-chloro-9-azido-1H-2,3,4,5-tetrahydro-3-benzazepine (SKF 102229), had a Ki for the human platelet alpha 2-adrenoceptor of approximately ... Full text Link to item Cite

Molecular mechanisms of receptor desensitization using the beta-adrenergic receptor-coupled adenylate cyclase system as a model.

Journal Article Nature · September 12, 1985 Desensitization, the tendency of biological responses to wane over time despite the continuous presence of a stimulus of constant intensity, is observed in organisms as diverse as bacteria and mammals. Recently, new insights into the molecular mechanisms u ... Full text Link to item Cite

Homologous desensitization of the beta-adrenergic receptor. Functional integrity of the desensitized receptor from mammalian lung.

Journal Article Mol Pharmacol · September 1985 Previous work has demonstrated that injection of rats with isoproterenol is rapidly (10 min) followed by the development of a homologous form of desensitization of the beta-agonist-coupled adenylate cyclase in lung membranes. Half the receptor pool becomes ... Link to item Cite

Phorbol esters promote alpha 1-adrenergic receptor phosphorylation and receptor uncoupling from inositol phospholipid metabolism.

Journal Article Proc Natl Acad Sci U S A · September 1985 DDT1 MF-2 cells, which are derived from hamster vas deferens smooth muscle, contain alpha 1-adrenergic receptors (54,800 +/- 2700 sites per cell) that are coupled to stimulation of inositol phospholipid metabolism. Incubation of these cells with tumor-prom ... Full text Open Access Link to item Cite

Transducin and the inhibitory nucleotide regulatory protein inhibit the stimulatory nucleotide regulatory protein mediated stimulation of adenylate cyclase in phospholipid vesicle systems.

Journal Article Biochemistry · August 13, 1985 The adenylate cyclase coupled inhibitory nucleotide regulatory protein (Ni) and the bovine retinal nucleotide regulatory protein transducin (T) appear to share some common functional properties since their GTPase activity is stimulated to similar extents b ... Full text Link to item Cite

Sensitization of frog erythrocyte adenylate cyclase system by tumor-promoting phorbol diesters.

Journal Article Can J Physiol Pharmacol · August 1985 Preincubation of frog erythrocyte lysates with tumor-promoting phorbol diesters leads to an increase in adenylate cyclase activity. This stimulatory effect of phorbol diesters was specific. Incubation with 12-O-tetradecanoylphorbol 13-acetate led to increa ... Full text Link to item Cite

Phosphorylation of the mammalian beta-adrenergic receptor by cyclic AMP-dependent protein kinase. Regulation of the rate of receptor phosphorylation and dephosphorylation by agonist occupancy and effects on coupling of the receptor to the stimulatory guanine nucleotide regulatory protein.

Journal Article J Biol Chem · June 10, 1985 In some systems, such as the turkey erythrocyte, agonist-promoted phosphorylation of the beta-adrenergic receptor appears to be associated with desensitization of the adenylate cyclase system. This process can be partially mimicked by cyclic AMP analogs. A ... Link to item Cite

Covalent labeling of the beta-adrenergic ligand-binding site with para-(bromoacetamidyl)benzylcarazolol. A highly potent beta-adrenergic affinity label.

Journal Article Mol Pharmacol · May 1985 para-(Bromoacetamidyl)benzylcarazolol (pBABC) was synthesized and found to be an extremely potent affinity label for beta-adrenergic receptors. Its interaction with mammalian (rabbit and hamster lung) and nonmammalian (turkey and frog erythrocyte) beta-adr ... Link to item Cite

Homologous desensitization of beta-adrenergic receptor coupled adenylate cyclase. Resensitization by polyethylene glycol treatment.

Journal Article J Biol Chem · April 25, 1985 Brief (approximately 20-min) exposure of S49 lymphoma cells to beta-agonists such as isoproterenol leads to a homologous form of desensitization in which beta-agonist but not prostaglandin E1-sensitive or NaF-sensitive adenylate cyclase is reduced. The des ... Link to item Cite

Homologous desensitization of adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor.

Journal Article J Biol Chem · April 10, 1985 We recently demonstrated that heterologous desensitization of adenylate cyclase in turkey erythrocytes is highly correlated with phosphorylation of the beta-adrenergic receptor. In contrast, little is known of the biochemical mechanisms underlying the homo ... Link to item Cite

The impact of aging on adrenergic receptor function: clinical and biochemical aspects.

Journal Article J Am Geriatr Soc · March 1985 From this discussion, several conclusions can be drawn. First, with advancing age there is a decrease in cardiovascular responsiveness and, more specifically, there is a decrease in catecholamine-stimulated chronotropic and inotropic responses. This decrea ... Full text Link to item Cite

Desensitization of the turkey erythrocyte beta-adrenergic receptor in a cell-free system. Evidence that multiple protein kinases can phosphorylate and desensitize the receptor.

Journal Article J Biol Chem · February 25, 1985 We have used a recently developed cell-free system (cell lysate) derived from turkey erythrocytes to explore the potential role of cAMP-activated and other protein kinase systems in desensitizing the adenylate cyclase-coupled beta-adrenergic receptor. Dese ... Link to item Cite

Specificity of the functional interactions of the beta-adrenergic receptor and rhodopsin with guanine nucleotide regulatory proteins reconstituted in phospholipid vesicles.

Journal Article J Biol Chem · February 10, 1985 We have assessed the functional interactions of two pure receptor proteins with three different pure guanine nucleotide regulatory proteins in phosphatidylcholine vesicles. The receptor proteins are the guinea pig lung beta-adrenergic receptor (beta AR) an ... Link to item Cite

Endogenous proteinases modulate the function of the beta-adrenergic receptor-adenylate cyclase system.

Journal Article Biochim Biophys Acta · December 20, 1984 Photoaffinity labeling techniques have recently demonstrated that mammalian beta 1- and beta 2-adrenergic receptors reside on peptides of Mr 62 000-64 000. These receptor peptides are susceptible to endogenous metalloproteinases which produce peptides of M ... Full text Link to item Cite

Enhanced adenylate cyclase activity of turkey erythrocytes following treatment with beta-adrenergic receptor antagonists.

Journal Article Eur J Pharmacol · December 15, 1984 The turkey erythrocyte contains a beta 1-adrenergic receptor-linked adenylate cyclase system. We have examined the effects of pretreatment with receptor antagonists on adenylate cyclase activity and the individual components in the pathway of enzyme activa ... Full text Link to item Cite

Photoaffinity labeling of beta-adrenergic receptors in mammalian tissues.

Journal Article Biochem Pharmacol · December 1, 1984 Photoaffinity labeling of beta 1- and beta 2-adrenergic receptors in plasma membranes from various mammalian tissues has been been performed utilizing the recently developed beta-adrenergic antagonist probe [125I]para-azidobenzylcarazolol. Tissues studied ... Full text Link to item Cite

Association of sequestered beta-adrenergic receptors with the plasma membrane: a novel mechanism for receptor down regulation.

Journal Article Life Sci · October 8, 1984 Chronic exposure of frog erythrocytes to beta-adrenergic agonists leads to desensitization of the responsiveness of adenylate cyclase to isoproterenol and is accompanied by "down-regulation", a decrease in the number of beta-adrenergic receptors on the cel ... Full text Link to item Cite

Translocation and uncoupling of the beta-adrenergic receptor in rat lung after catecholamine promoted desensitization in vivo.

Journal Article Endocrinology · October 1984 Beta-adrenergic agonists and antagonists are widely used in many clinical situations to regulate beta-adrenergic stimulation. However, responsiveness to beta-stimulation may be reduced by the process of desensitization. We have established an in vivo mamma ... Full text Link to item Cite

The mammalian beta 2-adrenergic receptor: reconstitution of functional interactions between pure receptor and pure stimulatory nucleotide binding protein of the adenylate cyclase system.

Journal Article Biochemistry · September 25, 1984 Pure beta-adrenergic receptors (beta-AR) isolated from guinea pig lung and pure guanine nucleotide binding regulatory protein (NS) of adenylate cyclase isolated from human erythrocytes have been inserted into phospholipid vesicles, resulting in the functio ... Full text Link to item Cite

The mammalian beta 2-adrenergic receptor: purification and characterization.

Journal Article Biochemistry · September 25, 1984 The beta 2-adrenergic receptors from hamster, guinea pig, and rat lungs have been solubilized with digitonin and purified by sequential Sepharose-alprenolol affinity and high-performance steric-exclusion liquid chromatography. Sodium dodecyl sulfate-polyac ... Full text Link to item Cite

Photoaffinity cross-linking of a radioiodinated probe, 125I-A55453, into alpha 1-adrenergic receptors.

Journal Article Mol Pharmacol · September 1984 We have synthesized and characterized a high-affinity alpha 1-adrenergic receptor probe, 4-amino-6,7-dimethoxy-2[4'- [5"(3"'-125I-iodo-4"'-aminophenyl)pentanoyl]-1'-piperazinyl] quinazoline (125I-A55453). This ligand binds reversibly to rat hepatic plasma ... Link to item Cite

Reconstitution of a hormone-sensitive adenylate cyclase system. The pure beta-adrenergic receptor and guanine nucleotide regulatory protein confer hormone responsiveness on the resolved catalytic unit.

Journal Article J Biol Chem · August 25, 1984 A hormone responsive adenylate cyclase has been reconstituted in phosphatidylcholine vesicles from its isolated protein components. The proteins used were the affinity chromatography purified (500-2000-fold) or pure Mr = 64,000 beta-adrenergic receptors (b ... Link to item Cite

Direct demonstration of impaired functionality of a purified desensitized beta-adrenergic receptor in a reconstituted system.

Journal Article Science · August 24, 1984 Long-term exposure of various cell types to beta-adrenergic agonists such as isoproterenol leads to an attenuated responsiveness ("desensitization") of the adenylate cyclase system to further challenge with these agonists. The turkey erythrocyte model syst ... Full text Link to item Cite

Desensitization of turkey erythrocyte adenylate cyclase. Beta-adrenergic receptor phosphorylation is correlated with attenuation of adenylate cyclase activity.

Journal Article J Biol Chem · August 10, 1984 Preincubation of turkey erythrocytes with beta-adrenergic agonists leads to an attenuation of the responsiveness of adenylate cyclase to subsequent hormonal stimulation. Recently, our laboratory has shown (Stadel, J. M., Nambi, P., Shorr, R. G. L., Sawyer, ... Link to item Cite

Mammalian beta-adrenergic receptors. Distinct glycoprotein populations containing high mannose or complex type carbohydrate chains.

Journal Article J Biol Chem · July 10, 1984 Mammalian beta-adrenergic receptor binding peptides can be visualized by covalently labeling them with the photoaffinity reagent p-azido-m-[125I]iodobenzylcarazolol followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. ... Link to item Cite

Development of an affinity ligand for purification of alpha 2-adrenoceptors from human platelet membranes.

Journal Article J Med Chem · July 1984 Human platelets contain alpha 2-adrenoceptors which are negatively coupled to the enzyme adenylate cyclase. In order to better understand the interaction of this subtype of alpha receptor with this key enzyme, we have initiated a program to isolate and cha ... Full text Link to item Cite

Phorbol diesters promote beta-adrenergic receptor phosphorylation and adenylate cyclase desensitization in duck erythrocytes.

Journal Article Biochem Biophys Res Commun · June 29, 1984 Preincubation of duck erythrocytes with tumor promoting phorbol diesters or catecholamines leads to attenuation of adenylate cyclase activity. 12-0-Tetradecanoyl phorbol-13-acetate (TPA) and phorbol 12,13-dibutyrate treatment induced a 38% and 30% desensit ... Full text Link to item Cite

Identification of the subunit-binding site of alpha 2-adrenergic receptors using [3H]phenoxybenzamine.

Journal Article J Biol Chem · June 25, 1984 alpha 2-Adrenergic receptors are members of an important class of membrane-bound receptors which appear to mediate physiologic responses by decreasing the activity of the regulatory enzyme adenylate cyclase. This report describes the first direct indentifi ... Link to item Cite

Effect of pertussis toxin on alpha 2-adrenoceptors: decreased formation of the high-affinity state for agonists.

Journal Article FEBS Lett · June 25, 1984 Administration of pertussis toxin to hamsters abolishes the alpha 2-adrenergic inhibition of adenylate cyclase in their adipocytes. The toxin did not modify the number of adipocyte alpha 2-adrenoceptors or their affinity for antagonists. In contrast, the a ... Full text Link to item Cite

Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.

Journal Article J Clin Invest · May 1984 Decreased activity of the guanine nucleotide regulatory protein (N) of the adenylate cyclase system is present in cell membranes of some patients with pseudohypoparathyrodism (PHP-Ia) whereas others have normal activity of N (PHP-Ib). Low N activity in PHP ... Full text Open Access Link to item Cite

Activation, desensitization, and recycling of frog erythrocyte beta-adrenergic receptors. Differential perturbation by in situ trypsinization.

Journal Article J Biol Chem · April 10, 1984 We have utilized limited in situ trypsinization of the adenylate cyclase-coupled beta-adrenergic receptor of frog erythrocytes to probe the processes of receptor activation, desensitization, and recycling. Treatment of intact erythrocytes with trypsin (1 m ... Link to item Cite

Cell-free desensitization of catecholamine-sensitive adenylate cyclase. Agonist- and cAMP-promoted alterations in turkey erythrocyte beta-adrenergic receptors.

Journal Article J Biol Chem · April 10, 1984 Conditions have been developed for desensitizing the beta-adrenergic receptor-coupled adenylate cyclase of turkey erythrocytes in a cell-free system. Desensitization is observed when cell lysates are incubated with isoproterenol or cAMP analogs for 30 min ... Link to item Cite

Morphologic demonstration of clathrin-coated pits in frog and turkey erythrocytes.

Journal Article Exp Cell Res · April 1984 We have examined nucleated erythrocytes of frog and turkey for the presence of clathrin-coated structures using electron microscopy and immunocytochemistry. By electron microscopy, coated pits were found on the plasma membrane of peripheral blood erythrocy ... Full text Link to item Cite

Photoaffinity labeling of turkey erythrocyte beta-adrenergic receptors: degradation of the Mr = 49,000 protein explains apparent heterogeneity.

Journal Article Biochem Biophys Res Commun · March 15, 1984 The potent photoaffinity probe [125I]p-azidobenzylcarazolol was used to identify beta-adrenergic receptors from turkey erythrocytes. Two peptides were specifically labeled with apparent Mr = 39,000 and 49,000 on sodium dodecyl sulfate polyacrylamide gel el ... Full text Link to item Cite

Photoaffinity labeling of mammalian alpha 1-adrenergic receptors. Identification of the ligand binding subunit with a high affinity radioiodinated probe.

Journal Article J Biol Chem · February 25, 1984 We have synthesized and characterized a novel high affinity radioiodinated alpha 1-adrenergic receptor photoaffinity probe, 4-amino-6,7-dimethoxy-2-[4-[5-(4-azido - 3 - [125I]iodophenyl) pentanoyl] - 1 - piperazinyl] quinazoline. In the absence of light, t ... Link to item Cite

Molecular biology of adrenergic receptors in the rat and frog central nervous system.

Journal Article Hypertension · 1984 Recent developments in the characterization of the adrenergic receptors have led to the identification and purification of the binding subunits of the various catecholamine receptors. beta-Adrenergic receptors have been identified in a wide variety of tiss ... Full text Link to item Cite

Structure and function of beta-adrenergic receptors: regulation at the molecular level.

Journal Article Adv Cyclic Nucleotide Protein Phosphorylation Res · 1984 Link to item Cite

Molecular biology of adrenergic receptors in the rat and frog central nervous system

Journal Article Hypertension · 1984 Recent developments in the characterization of the adrenergic receptors have led to the identification and purification of the binding subunits of the various catecholamine receptors. β-Adrenergic receptors have been identified in a wide variety of tissues ... Cite

Determination of the Molecular Size of Frog and Turkey Erythrocyte β-Adrenergic Receptors by Radiation Inactivation

Journal Article Biochemistry · January 1, 1984 The β1 and β2-adrenergic receptors from turkey and frog erythrocyte plasma membranes, respectively, have been solubilized with digitonin and purified by sequential affinity and gel-permeation high-performance liquid chromatography. Examination of these pre ... Full text Cite

Cardiac adrenergic receptors.

Journal Article Annu Rev Med · 1984 Recently developed pharmacological and biochemical techniques have brought new insights about the structure, function, and regulation of beta-adrenergic receptors. This chapter focuses on the cardiac beta-adrenergic receptor and the possible clinical and p ... Full text Link to item Cite

Pure beta-adrenergic receptor: the single polypeptide confers catecholamine responsiveness to adenylate cyclase.

Journal Article Nature · December 8, 1983 The beta-adrenergic receptor binding subunits from frog erythrocytes, hamster lung and guinea pig lung have been purified to apparent homogeneity and in all cases reside on a single polypeptide. Insertion of the pure receptors into phospholipid vesicles an ... Full text Link to item Cite

Solubilization of rat liver alpha 1-adrenergic receptors. Agonist specific alteration in receptor binding affinity.

Journal Article Biochem Pharmacol · November 1, 1983 An improved method for the solubilization of the alpha 1-adrenergic receptors in rat liver, utilizing digitonin, glycerol and sonication, is described. The yield of solubilized receptors was approximately 20%. The soluble receptors showed characteristics s ... Full text Link to item Cite

The beta-adrenergic receptor in heart failure.

Journal Article Hosp Pract (Off Ed) · November 1983 Although the role of the autonomic nervous system in the pathophysiology of heart failure has been studied for decades, only within the past few years have adrenergic receptors and their alterations occupied center stage. There is now considerable evidence ... Full text Link to item Cite

Plasma membrane receptors.

Journal Article J Clin Invest · October 1983 Full text Link to item Cite

Covalent labeling of the cerebral cortex alpha 1-adrenergic receptor with a new high affinity radioiodinated photoaffinity probe.

Journal Article Biochem Biophys Res Commun · September 30, 1983 A novel high affinity radioiodinated photoaffinity probe, 4-amino-6,7-dimethoxy-2[4-[5(3-[125I]iodo-4-azidophenyl)pentanoyl]-1- piperazinyl]-quinazoline, structurally related to the potent alpha 1-adrenergic antagonist prazosin, was developed and used to c ... Full text Link to item Cite

Mammalian beta-adrenergic receptors. Structural differences in beta 1 and beta 2 subtypes revealed by peptide maps.

Journal Article J Biol Chem · September 10, 1983 Photoaffinity labeling techniques using p-azido-m-[125I]iodobenzylcarazolol have recently demonstrated that both the beta 1- and beta 2-adrenergic receptor-binding subunits from mammalian tissues including heart, lung, and erythrocytes reside on peptides o ... Link to item Cite

Activation of adenylate cyclase by beta-adrenergic receptors: investigation of rate limiting steps by simultaneous assay of high affinity agonist binding and GDP release.

Journal Article Life Sci · September 5, 1983 We report the development and application of a novel assay for high affinity binding of the agonist [3H]hydrozybenzyl-isoproterenol simultaneously with the agonist-promoted release of membrane bound [32P]GDP in the frog erythrocyte beta-adrenergic receptor ... Full text Link to item Cite

Guanine nucleotides modulate the binding affinity of the oligopeptide chemoattractant receptor on human polymorphonuclear leukocytes.

Journal Article J Clin Invest · September 1983 The oligopeptide chemoattractant receptor on human polymorphonuclear leukocyte (PMN) membranes exists in two affinity states. Since guanine nucleotides regulate the binding affinity and transductional activity of several other types of receptors, we examin ... Full text Link to item Cite

Polymorphonuclear leukocyte function in psoriasis: chemotaxis, chemokinesis, beta-adrenergic receptors, and proteolytic enzymes of polymorphonuclear leukocytes in the peripheral blood from psoriatic patients.

Journal Article J Invest Dermatol · September 1983 Psoriatic patients, particularly those with psoriatic arthritis, have neutrophilic and eosinophilic leukocytosis. Isolated polymorphonuclear leukocytes (PMNLs) from psoriatic patients have normal concentrations of proteolytic enzymes and they have beta-adr ... Full text Link to item Cite

Reconstitution of beta-adrenergic receptors in lipid vesicles: affinity chromatography-purified receptors confer catecholamine responsiveness on a heterologous adenylate cyclase system.

Journal Article Proc Natl Acad Sci U S A · August 1983 The binding function of purified receptors can be assessed with radioligands, but the interaction of receptors with their biochemical effectors has not been amenable to direct study. Toward this end, procedures have been developed for directly demonstratin ... Full text Link to item Cite

Human cardiac beta-adrenergic receptors: subtype heterogeneity delineated by direct radioligand binding.

Journal Article Life Sci · August 1, 1983 Human myocardial beta-adrenergic receptors were directly identified and characterized using the high affinity antagonist radioligand [125I]iodocyanopindolol. Beta 1 and beta 2 adrenergic receptors were found to coexist in both the left ventricle and right ... Full text Link to item Cite

The cardiac beta-adrenergic receptor. Structural similarities of beta 1 and beta 2 receptor subtypes demonstrated by photoaffinity labeling.

Journal Article J Biol Chem · July 10, 1983 The beta-adrenergic receptor photoaffinity ligand p-azido-m-[125I]iodobenzylcarazolol has been used to covalently label the beta 1 and beta 2 adrenergic receptor binding subunits present in left ventricular myocardial membranes derived from mammalian (incl ... Link to item Cite

Functional modification of the guanine nucleotide regulatory protein after desensitization of turkey erythrocytes by catecholamines.

Journal Article Arch Biochem Biophys · July 1, 1983 Densensitization of turkey erythrocytes by exposure to the beta-adrenergic agonist (-)isoproterenol leads to decreased activation of adenylate cyclase by agonist, NaF, and guanyl-5'-yl imido diphosphate, with no reduction in the number of beta-adrenergic r ... Full text Link to item Cite

Catecholamine-induced desensitization of turkey erythrocyte adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · June 1983 Preincubation of turkey erythrocytes with catecholamines desensitizes the beta-adrenergic receptor-adenylate cyclase complex in the plasma membranes of these cells. Photoaffinity labeling of the beta-adrenergic receptors with 125I-labeled p-azidobenzylcara ... Full text Link to item Cite

Synthesis of iodine-125 labeled (+/-)-15-(4-azidobenzyl)carazolol: a potent beta-adrenergic photoaffinity probe.

Journal Article J Med Chem · June 1983 (+/-)-15-(4-Azidobenzyl)carazolol (2), a potent beta-adrenergic photoaffinity ligand developed in our laboratories, has been radioiodinated to theoretical specific activity (2175 Ci/mmol) and shown to label covalently beta-adrenergic receptor peptides in a ... Full text Link to item Cite

Functional integrity of desensitized beta-adrenergic receptors.

Journal Article J Biol Chem · May 25, 1983 The adenylate cyclase-coupled beta 2-adrenergic receptor of the frog erythrocyte has served as a useful model system for elucidating the mechanisms of catecholamine-induced densensitization. In this system, it has been previously demonstrated that agonist- ... Link to item Cite

Antibodies to the beta-adrenergic receptor: attenuation of catecholamine-sensitive adenylate cyclase and demonstration of postsynaptic receptor localization in brain.

Journal Article Proc Natl Acad Sci U S A · April 1983 Antibodies to the beta 2-adrenergic receptor of frog erythrocytes have been raised in rabbits by immunization with purified receptor preparations. Binding of the antibodies to the receptors was demonstrated by immunoprecipitation and by the altered mobilit ... Full text Link to item Cite

In vitro desensitization of beta adrenergic receptors in human neutrophils. Attenuation by corticosteroids.

Journal Article J Clin Invest · March 1983 The receptor alterations involved in catecholamine-induced desensitization of adenylate cyclase in human neutrophils have been investigated as has the ability of hydrocortisone to modify such alterations. Incubation of human neutrophils with isoproterenol ... Full text Link to item Cite

Photoaffinity labelling of mammalian beta-adrenergic receptors: metal-dependent proteolysis explains apparent heterogeneity.

Journal Article Biochem Biophys Res Commun · January 27, 1983 The beta-adrenergic receptors in membranes from rat and hamster lungs have been studies using the photoaffinity label p-azido-m-[125I]-iodobenzyl-carazolol. Previous work with several beta adrenergic photoaffinity probes has suggested heterogeneity of the ... Full text Link to item Cite

The β-Adrenergic Receptor: Ligand Binding Studies Illuminate the Mechanism of Receptor-Adenylate Cyclase Coupling

Journal Article Current Topics in Membranes and Transport · January 1, 1983 This chapter relates the study of adrenergic receptors to the regulation of adenylate cyclase activity. The ubiquitous nature of the adrenergic responses has made these systems prototypes or models for the study of receptor-effector coupling in general. Pr ... Full text Cite

PHOTOAFFINITY-LABELING OF THE HUMAN MYOCARDIAL BETA-ADRENERGIC-RECEPTOR

Journal Article JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY · January 1, 1983 Link to item Cite

ALPHA-ADRENOCEPTOR AFFINITY LIGANDS

Journal Article ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · January 1, 1983 Link to item Cite

PHOTOAFFINITY-LABELING OF BETA-ADRENERGIC RECEPTORS IN MAMMALIAN-TISSUES

Journal Article FEDERATION PROCEEDINGS · January 1, 1983 Link to item Cite

PARTIAL-PURIFICATION OF THE HUMAN-PLATELET ALPHA2-ADRENERGIC RECEPTOR

Journal Article FEDERATION PROCEEDINGS · January 1, 1983 Link to item Cite

NOT NECESSARILY ABOUT RECEPTORS

Journal Article CLINICAL RESEARCH · January 1, 1983 Link to item Cite

Affinity chromatography of human platelet alpha 2-adrenergic receptors.

Journal Article Proc Natl Acad Sci U S A · December 1982 Catecholamines, such as epinephrine, inhibit the enzyme adenylate cyclase (EC 4.6.1.1) via a specific receptor mechanism involving alpha(2)-adrenergic receptors. In order to facilitate purification of these inhibitory receptors we have prepared a highly ef ... Full text Link to item Cite

The β1-adrenergic receptor of the turkey erythrocyte. Molecular heterogeneity revealed by purification and photoaffinity labeling

Journal Article Journal of Biological Chemistry · December 1, 1982 The β1-adrenergic receptor of turkey erythrocytes has been purified by a combination of affinity and high performance steric exclusion chromatography. These procedures provide preparations with specific activities of > 15,000 pmol/mg of protein with an ove ... Cite

The beta 1-adrenergic receptor of the turkey erythrocyte. Molecular heterogeneity revealed by purification and photoaffinity labeling.

Journal Article J Biol Chem · October 25, 1982 The beta 1-adrenergic receptor of turkey erythrocytes has been purified by a combination of affinity and high performance steric exclusion chromatography. These procedures provide preparations with specific activities of greater than 15,000 pmol/mg of prot ... Link to item Cite

Catecholamine-induced desensitization of turkey erythrocyte adenylate cyclase. Structural alterations in the beta-adrenergic receptor revealed by photoaffinity labeling.

Journal Article J Biol Chem · August 25, 1982 Preincubation of turkey erythrocytes with isoproterenol results in an impaired ability of beta-adrenergic agonists to stimulate adenylate cyclase in membranes prepared from these cells. The biochemical basis for this agonist-induced desensitization was inv ... Link to item Cite

Mechanisms of hormone receptor-effector coupling: the beta-adrenergic receptor and adenylate cyclase.

Journal Article Fed Proc · August 1982 The beta-adrenergic receptors that are coupled to adenylate cyclase have provided a model system for studying the mechanisms by which a plasma membrane receptor is coupled to a well-defined biochemical effector. The beta 2-adrenergic receptors from frog er ... Link to item Cite

Molecular characterization of the beta-adrenergic receptor of frog erythrocytes.

Journal Article Metabolism · July 1982 The beta-adrenergic receptor of the frog erythrocyte has been solubilized in an active form with digitonin and purified by affinity chromatography and high performance liquid chromatography. Purified preparations contain a single band of iodinated protein ... Full text Link to item Cite

Clinical physiology of adrenergic receptor regulation.

Journal Article Am J Physiol · July 1982 Radioligand binding studies now permit the direct investigation of the alpha- and beta-adrenergic receptors. The concentration of the receptors in cell membranes is modulated by a wide variety of physiological and pathophysiological variables and may be ei ... Full text Link to item Cite

The beta-adrenergic receptor: rapid purification and covalent labeling by photoaffinity crosslinking.

Journal Article Proc Natl Acad Sci U S A · May 1982 New procedures for the rapid purification and covalent labeling of the beta-adrenergic receptors have been developed that should greatly accelerate progress in the study of these widely distributed adenylate cyclase-coupled receptors. Chromatography of sol ... Full text Link to item Cite

Interactions of agonists with platelet alpha 2-adrenergic receptors.

Journal Article Endocrinology · March 1982 Epinephrine induces human platelet aggregation by interacting with alpha-adrenergic receptors. These sites were demonstrated by radioligand-binding techniques using the new antagonist ligand, [3H]yohimbine. The sites labeled by [3H]yohimbine had the specif ... Full text Link to item Cite

Reciprocal modulation of agonist and antagonist binding to muscarinic cholinergic receptor by guanine nucleotide.

Journal Article Proc Natl Acad Sci U S A · March 1982 The ability of guanine nucleotide to decrease the binding affinity of agonists but not antagonists has been documented in a number of hormone and neurotransmitter receptor systems. By contrast, recent reports indicate that both agonist and antagonist bindi ... Full text Link to item Cite

Agonist interactions with alpha-adrenergic receptors.

Journal Article J Cardiovasc Pharmacol · 1982 alpha-Adrenergic receptors have been grouped into two major subtypes, termed alpha 1- and alpha 2-receptors. Radioligand binding techniques have been utilized to measure the number of alpha 1- and alpha 2-receptors in a variety of tissues. [3H]Dihydroergoc ... Full text Link to item Cite

Adrenergic receptors in the heart.

Journal Article Annu Rev Physiol · 1982 Full text Link to item Cite

REGULATION OF ADENYLATE-CYCLASE BY ADRENERGIC-RECEPTORS

Journal Article BIOCHEMICAL ACTIONS OF HORMONES · January 1, 1982 Link to item Cite

The β1-adrenergic receptor of the turkey erythrocyte. Molecular heterogeneity revealed by purification and photoaffinity labeling

Journal Article Journal of Biological Chemistry · 1982 The β1-adrenergic receptor of turkey erythrocytes has been purified by a combination of affinity and high performance steric exclusion chromatography. These procedures provide preparations with specific activities of > 15,000 pmol/mg of protein with an ... Cite

Effect of thyroid status on alpha- and beta-catecholamine responsiveness of hamster adipocytes.

Journal Article Biochim Biophys Acta · December 18, 1981 It has been suggested that part of the increased beta-catecholamine responsiveness in hyperthyroid animals is due to a decrease in alpha-catecholamine action. The present results indicate that neither hyperthyroidism nor hypothyroidism altered the alpha 2- ... Full text Link to item Cite

Hypothyroidism modulates beta adrenergic receptor adenylate cyclase interactions in rat reticulocytes.

Journal Article J Clin Invest · December 1981 We have investigated alterations in beta adrenergic receptor binding sites of rat reticulocytes occurring in animals rendered hypothyroid by thyroidectomy. Beta adrenergic receptor interactions were assessed by measuring the number of (-)[3H]-dihydroalpren ... Full text Link to item Cite

Photoaffinity labeling of the beta-adrenergic receptor.

Journal Article J Biol Chem · November 25, 1981 A new photoactive beta-adrenergic antagonist, p-azidobenzylcarazolol (pABC) has been synthesized by combining a carbazole moiety with a p-azido-benzyl substituent. The compound has been labeled with tritium to a specific activity of 26 Ci/mmol. In frog ery ... Link to item Cite

Agonist-promoted high affinity state of the beta-adrenergic receptor in human neutrophils: modulation by corticosteroids.

Journal Article J Clin Endocrinol Metab · October 1981 beta-Adrenergic agonists form high affinity complexes with receptors, resulting in activation of the associated adenylate cyclase. To examine the formation of the high affinity state of the receptor, curves were constructed for the competition of the full ... Full text Link to item Cite

Evidence that a beta-adrenergic receptor-associated guanine nucleotide regulatory protein conveys guanosine 5'-O-(3-thiotriphosphate)- dependent adenylate cyclase activity.

Journal Article J Biol Chem · August 25, 1981 The guanine nucleotide regulatory protein component (N) of the frog erythrocyte membrane adenylate cyclase system appears to form a stable complex with the beta-adrenergic receptor (R) in the presence of agonist (H). This agonist-promoted ternary complex H ... Link to item Cite

alpha-Adrenergic receptors in human adipocyte membranes: direct determination by [3H]yohimbine binding.

Journal Article J Clin Endocrinol Metab · April 1981 The presence of alpha 2-adrenergic receptors in membranes derived from human sc adipose tissue was directly demonstrated with a new alpha 2-selective ligand, [3H]yohimbine. Binding of this radiolabeled antagonist to adipocyte membranes was of high affinity ... Full text Link to item Cite

Myocardial beta-adrenergic receptors from adrenalectomized rats: impaired formation of high-affinity agonist-receptor complexes.

Journal Article Endocrinology · February 1981 Adrenal steroid hormones potentiate beta-adrenergic actions on the heart. Accordingly, we investigated the effects of adrenalectomy on agonist and antagonist interactions with myocardial beta-adrenergic receptors and adenylate cyclase. The affinity and num ... Full text Link to item Cite

Pharmacological characterizations of adrenergic receptors in human adipocytes.

Journal Article J Clin Invest · February 1981 Three types of adrenergic receptors, beta, alpha-1, and alpha-2, were identified in human adipocytes, isolated from properitoneal adipose tissue, using both the binding of radioactive ligands and the effects of adrenergic agents on receptor-specific bioche ... Full text Link to item Cite

Molecular properties of the purified beta-adrenergic receptor

Journal Article Federation Proceedings · January 1, 1981 Cite

Regulation of insulin receptors in frog erythrocytes by insulin and concanavalin A

Journal Article Journal of Supramolecular and Cellular Biochemistry · January 1, 1981 Cite

Differential effects of cholera toxin on guanine nucleotide regulation of beta-adrenergic agonist high affinity binding and adenylate cyclase activation in frog erythrocyte membranes.

Journal Article J Cyclic Nucleotide Res · 1981 The guanine nucleotide regulatory protein(s) regulates both adenylate cyclase activity and the affinity of adenylate cyclase-coupled receptors for hormones or agonist drugs. Cholera toxin catalyzes the covalent modification of the nucleotide regulatory pro ... Link to item Cite

Subtype specificity of alpha-adrenergic receptors in rat heart.

Journal Article J Cardiovasc Pharmacol · 1981 Recent studies suggest that two subtypes of alpha-adrenergic receptors (alpha 1 and alpha 2) can be distinguished on the basis of the differential affinities of certain adrenergic ligands for each subtype. We have investigated the binding characteristics o ... Full text Link to item Cite

PHOTOAFFINITY-LABELING OF THE BETA-ADRENERGIC-RECEPTOR

Journal Article JOURNAL OF BIOLOGICAL CHEMISTRY · January 1, 1981 Link to item Cite

MOLECULAR-PROPERTIES OF THE PURIFIED BETA-ADRENERGIC-RECEPTOR

Journal Article FEDERATION PROCEEDINGS · January 1, 1981 Link to item Cite

POLYMORPHONUCLEAR LEUKOCYTE FUNCTIONS IN PSORIASIS

Journal Article CLINICAL RESEARCH · January 1, 1981 Link to item Cite

Catecholamine-induced desensitization in turkey erythrocytes: cAMP mediated impairment of high affinity agonist binding without alteration in receptor number.

Journal Article J Cyclic Nucleotide Res · 1981 Desensitization of turkey erythrocyte adenylate cyclase by exposure of these cells to the beta-adrenergic agonist isoproterenol leads to a decrease in subsequent adenylate cyclase stimulation by isoproterenol, F-, or Gpp(NH)p without any apparent loss or d ... Link to item Cite

Differential regulation of the alpha 2-adrenergic receptor by Na+ and guanine nucleotides.

Journal Article Nature · December 25, 1980 Many hormones interact with receptors which stimulate the enzyme adenylate cyclase. Less well characterized ar those receptors which mediate an inhibition of adenylate cyclase activity. However, guanine nucleotides are clearly important in the regulation o ... Full text Link to item Cite

Use of cell fusion techniques to probe the mechanism of catecholamine-induced desensitization of adenylate cyclase in frog erythrocytes.

Journal Article Biochim Biophys Acta · October 15, 1980 The catecholamine-sensitive adenylate cyclase system appears to be comprised of at least three components; the beta-adrenergic receptor (R component), the catalytic unit of adenylate cyclase (C component) and a nucleotide regulatory protein (N component), ... Full text Link to item Cite

Corticosteroid-induced differential regulation of beta-adrenergic receptors in circulating human polymorphonuclear leukocytes and mononuclear leukocytes.

Journal Article J Clin Endocrinol Metab · September 1980 A method of reproducibility measuring human leukocyte beta-adrenergic receptor density and affinity has been developed and applied to the study of receptor regulation in man. The method has the advantages of using a membrane preparation which binds highly ... Full text Link to item Cite

A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor.

Journal Article J Biol Chem · August 10, 1980 The unique properties of agonist binding to the frog erythrocyte beta-adrenergic receptor include the existence of two affinity forms of the receptor. The proportion and relative affinity of these two states of the receptor for ligands varies with the intr ... Link to item Cite

Agonist versus antagonist binding to alpha-adrenergic receptors.

Journal Article Proc Natl Acad Sci U S A · August 1980 The binding properties of two alpha-adrenergic radioligands, [3H]epinephrine (an agonist) and [3H]dihydroergocryptine (an antagonist), were compared in two model systems--membranes derived from human platelets and membranes from rat liver. The platelet con ... Full text Link to item Cite

Peripheral alpha-adrenergic receptor subtypes.

Journal Article Psychopharmacol Bull · July 1980 Link to item Cite

Alpha-adrenergic receptor subtypes.

Journal Article N Engl J Med · June 19, 1980 Full text Link to item Cite

The human placenta--a rich source of beta-adrenergic receptors: characterization of the receptors in particulate and solubilized preparations.

Journal Article J Clin Endocrinol Metab · June 1980 A crude particulate fraction of human placenta possesses a high concentration of beta-adrenergic receptors, as determined by (-)-[3H]dihydroalprenolol binding (approximately 240 fmol/mg protein; Kd approximately 2 nM). The sites display all the typical cha ... Full text Link to item Cite

Effects of local anesthetics on guanyl nucleotide modulation of the catecholamine-sensitive adenylate cyclase system and on beta-adrenergic receptors.

Journal Article Biochim Biophys Acta · May 7, 1980 Tetracaine and other local anesthetics exert multiple actions on the catecholamine-sensitive adenylate cyclase system of frog erythrocyte membranes. Tetracaine (0.2--20 mM) reduces the responsiveness of adenylate cyclase to (a) guanyl-5'-yl-imidodiphosphat ... Full text Link to item Cite

Macromolecular beta-adrenergic antagonists discriminating between receptor and antibody.

Journal Article Proc Natl Acad Sci U S A · April 1980 The beta-adrenergic antagonist, alprenolol, was attached in an irreversible manner to macromolecular dextran via side arms that differed in length. The ability of these macromolecules to bind to the beta-adrenergic receptor of frog erythrocytes and to cate ... Full text Link to item Cite

Agonist-promoted coupling of the beta-adrenergic receptor with the guanine nucleotide regulatory protein of the adenylate cyclase system.

Journal Article Proc Natl Acad Sci U S A · February 1980 Binding of the beta-adrenergic agonist [3H]hydroxybenzylisoproterenol to the beta-adrenergic receptor of rat reticulocyte membranes results in the coupling of the receptor to the guanine nucleotide regulatory protein associated with the adenylate cyclase s ... Full text Link to item Cite

Beta adrenergic receptors in lymphocyte subpopulations.

Journal Article J Allergy Clin Immunol · January 1980 To further evaluate the potential utility of lymphocyte beta adrenergic receptor assays in the study of receptor alterations in human disease, we studied highly purified populations of B and T lymphocytes in peripheral blood to see if differences existed i ... Full text Link to item Cite

Recent Developments in Adrenergic Receptor Research

Journal Article Annual Reports in Medicinal Chemistry · January 1, 1980 Virtually all the physiological effects of catecholamines, generally termed adrenergic effects, could be classified as being of the two major types. These two types of responses are termed as “α”- and “β”-adrenergic, respectively, and hypothesized that the ... Full text Cite

New directions in adrenergic receptor research part II

Journal Article Trends in Pharmacological Sciences · January 1, 1980 Full text Cite

New directions in adrenergic receptor research. Part I

Journal Article Trends in Pharmacological Sciences · January 1, 1980 Full text Cite

Anomalous binding properties of high affinity racemic radio-ligands

Journal Article Federation Proceedings · January 1, 1980 Cite

Adrenergic receptors.

Journal Article Adv Cyclic Nucleotide Res · 1980 Link to item Cite

SUBTYPE SPECIFICITY OF ALPHA ADRENERGIC-RECEPTORS IN RAT-HEART

Journal Article CLINICAL RESEARCH · January 1, 1980 Link to item Cite

ANOMALOUS BINDING-PROPERTIES OF HIGH-AFFINITY RACEMIC RADIOLIGANDS

Journal Article FEDERATION PROCEEDINGS · January 1, 1980 Link to item Cite

Biochemical characterization of the beta-adrenergic receptor of the frog erythrocyte.

Journal Article Mol Cell Biochem · December 14, 1979 The beta-adrenergic receptor which is coupled to adenylate cyclase in the frog erythrocyte plasma membrane provides a convenient model system for probing the molecular characteristics of an adenylate cyclase coupled hormone receptor. Direct radioligand bin ... Full text Link to item Cite

Beta adrenergic and muscarinic cholinergic receptors in canine myocardium. Effects of ischemia.

Journal Article J Clin Invest · November 1979 Experimental myocardial ischemia produced in dogs by proximal left anterior descending coronary artery ligation is accompanied by relatively rapid (1 h) increases in the number of (-) [3H]dihydroalprenolol binding sites without changing their dissociation ... Full text Link to item Cite

Desensitization of beta-adrenergic stimulated adenylate cyclase in turkey erythrocytes.

Journal Article J Cyclic Nucleotide Res · October 1979 Desensitization of catecholamine stimulated adenylate cyclase (AC) activity is demonstrated in membranes derived from turkey erythrocytes pre-treated with isoproterenol. Membranes from desensitized cells had a loss in maximal catecholamine stimulated adeny ... Link to item Cite

Multiple effects of guanine nucleotides on human platelet adenylated cyclase.

Journal Article Biochim Biophys Acta · September 20, 1979 We report that the adenylate cyclase system in human platelets is subject to multiple regulation by guanine nucleotides. Previously it has been reported that GTP is either required for or has little effect on the response of the enzyme to prostaglandin E1. ... Full text Link to item Cite

Direct binding studies of adrenergic receptors: biochemical, physiologic, and clinical implications.

Journal Article Ann Intern Med · September 1979 Recently developed radioligand binding techniques permit direct investigation of the alpha- and beta-adrenergic receptors for catecholamines in a wide variety of tissues. These techniques allow the receptors to be quantitated, characterized, and studied un ... Full text Link to item Cite

Differential effects of GTP on the coupling of beta-adrenergic receptors to adenylate cyclase from frog and turkey erythrocytes. Application of new methods for the analysis of receptor-effector coupling.

Journal Article Biochim Biophys Acta · August 22, 1979 A detailed comparison of the interaction of beta-adrenergic receptors with adenylate cyclase stimulation and modification of this interaction by guanine nucleotides has been made in two model systems, the frog and turkey erythrocyte. Objective analysis of ... Full text Link to item Cite

Antibodies raised against purified beta-adrenergic receptors specifically bind beta-adrenergic ligands.

Journal Article Proc Natl Acad Sci U S A · May 1979 Antibodies raised against purified beta-adrenergic receptors themselves specifically bind beta-adrenergic ligands. Digitonin-solubilized frog (Rana pipiens) erythrocyte beta-adrenergic receptors, purified 100- to 200-fold by adsorption to an alprenolol-aga ... Full text Link to item Cite

Affinity chromatography of the beta-adrenergic receptor.

Journal Article J Biol Chem · April 25, 1979 Link to item Cite

Beta-Adrenergic receptors of human lymphocytes are unaltered by hyperthyroidism.

Journal Article J Clin Endocrinol Metab · March 1979 Lymphocytes from 12 patients with untreated hyperthyroidism were compared to lymphocytes from age- and sex-matched euthyroid control subjects to test the hypothesis that alterations in beta-adrenergic response mechanisms occur in human hyperthyroidism. The ... Full text Link to item Cite

POLYMERIC DRUG BY DIRECT CO-POLYMERIZATION: POLYMER OF beta -ADRENERGIC ANTAGONIST AND ITS BINDING TO RECEPTOR AND ANTIBODY.

Journal Article American Chemical Society, Polymer Preprints, Division of Polymer Chemistry · January 1, 1979 Water-soluble polymeric drugs are often prepared by complex procedures. The same applies to the preparation of resin-anchored drugs used in the affinity chromatogrphy of drug receptors. In some instances a more direct approach may result in a considerable ... Cite

Thyroid hormone regulation of alpha-adrenergic receptors: studies in rat myocardium.

Journal Article J Cardiovasc Pharmacol · 1979 The effects of alterations in thyroid state on cardiac alpha-adrenergic receptors were investigated by the binding of [3H]dihydroergocryptine (DHE), a potent alpha-adrenergic antagonist. In seven experiments, cardiac membranes from euthyroid rats bound 47 ... Full text Link to item Cite

Influence of experimental myocardial ischemia on beta adrenergic receptors

Journal Article American Journal of Cardiology · January 1, 1979 Cite

Influence of experimental myocardial ischemia on beta adrenergic receptors

Journal Article Journal of Molecular and Cellular Cardiology · January 1, 1979 Full text Cite

Beta-adrenergic receptors determine affinity but not intrinsic activity of drugs

Journal Article Federation Proceedings · January 1, 1979 Cite

Physical conditioning and membrane receptors for cardioregulatory hormones

Journal Article Clinical Research · January 1, 1979 Cite

The molecular size of adenylate cyclase in the absence and presence of nucleotide and hormone effectors.

Journal Article J Cyclic Nucleotide Res · 1979 The molecular size of adenylate cyclase solubilized from frog erythrocyte membranes by digitonin extraction has been determined by chromatography on Sepharose 6B. Regardless of whether the membranes are exposed to catecholamines, GPP(NH)P, NaF or no effect ... Link to item Cite

Alpha-adrenergic receptors in rat myocardium. Identification by binding of [3H]dihydroergocryptine.

Journal Article Circ Res · November 1978 [3H]Dihydroergocryptine ([3H]DHE) binds to sites in membranes derived from rat myocardium that have the characteristics expected of alpha-adrenergic receptors. The binding is saturable with 41 fmol [3H]DHE bound per mg of protein and of high affinity with ... Full text Link to item Cite

Hepatic alpha-adrenergic receptors. Identification and subcellular localization using [3H]dihydroergocryptine.

Journal Article J Biol Chem · September 10, 1978 Recently, several workers have shown that adrenergic control of hepatic carbohydrate metabolism has the characteristics of an alpha-receptor-mediated process. Using the rat liver membrane preparation of Neville (Neville, D. (1968) Biochim. Biophys. Acta 15 ... Link to item Cite

Differences between agonist and antagonist binding following beta-adrenergic receptor desensitization.

Journal Article J Biol Chem · May 25, 1978 The specific beta-adrenergic agonist radioligand (+/-)-[3H]hydroxybenzylisoproterenol ([3H]HBI) was used to investigate alterations in the beta-adrenergic receptors of frog erythrocytes occurring during the process of agonist-induced, receptor-specific des ... Link to item Cite

Multiple effects of N, N' dicyclohexyl carbodiimide on the beta-adrenergic receptor--adenylate cyclase system in frog erythrocytes.

Journal Article J Cyclic Nucleotide Res · February 1978 Treatment of frog erythrocytes with N,N' dicyclohexylcarbodiimide (DCCD) leads to a loss of catecholamine stimulated adenylate cyclase activity without any decrease in fluoride or PGE1 stimulated cyclase. However, the concentrations of the reagent which in ... Link to item Cite

Identification of alpha-adrenergic receptors in human platelets by [3H]dihydroergocryptine binding.

Journal Article J Clin Invest · February 1978 Binding of [(3)H]dihydroergocryptine to platelet lysates appears to have all the characteristics of binding to alpha-adrenergic receptors. At 25 degrees C binding reaches equilibrium within 20 min and is reversible upon addition of excess phentolamine. Bin ... Full text Link to item Cite

Identification and regulation of alpha- and beta-adrenergic receptors.

Journal Article Fed Proc · February 1978 Direct radioligand binding methods for studying the alpha- and beta-adrenergic receptors have been developed over the past several years. These techniques use radioactively labeled adrenergic antagonists and agonists to identify the receptors in appropriat ... Link to item Cite

[3H-Ddihydroergocryptine binding to alpha adrenergic receptors in canine aortic membranes

Journal Article Journal of Pharmacology and Experimental Therapeutics · 1978 [3H]Dihydroergocryptine, a potent alpha adrenergic antagonist, was used to label alpha adrenergic receptors in membranes isolated from dog aortas. Binding reached steady state in 4 minutes at 25° C and was completely reversible. At saturation the total num ... Cite

Agonist induced increase in apparent β-adrenergic receptor size

Journal Article Federation Proceedings · January 1, 1978 Cite

Agonist-induced increase in apparent beta-adrenergic receptor size.

Journal Article Proc Natl Acad Sci U S A · January 1978 The properties of digitonin-solubilized beta-adrenergic receptors from frog erythrocyte membranes were studied by gel exclusion chromatography on AcA 34 Ultragel. beta-Adrenergic receptor binding activity in these membranes can be identified by both an ago ... Full text Link to item Cite

Beta-adrenergic receptors: regulatory role of agonists.

Journal Article J Supramol Struct · 1978 Direct radioligand binding studies have been used to probe the molecular mechanisms whereby agonist catecholamines regulate the function of beta-adrenergic receptors in a model system, the frog erythrocyte. The unique characteristics of agonist as opposed ... Full text Link to item Cite

AGONIST INDUCED INCREASE IN APPARENT BETA-ADRENERGIC-RECEPTOR SIZE

Journal Article FEDERATION PROCEEDINGS · January 1, 1978 Link to item Cite

BIOCHEMICAL EFFECTS OF THYROID STATE ON CARDIAC SARCOLEMMA (SL)

Journal Article FEDERATION PROCEEDINGS · January 1, 1978 Link to item Cite

[3H-Ddihydroergocryptine binding to alpha adrenergic receptors in canine aortic membranes

Journal Article Journal of Pharmacology and Experimental Therapeutics · January 1, 1978 [3H]Dihydroergocryptine, a potent alpha adrenergic antagonist, was used to label alpha adrenergic receptors in membranes isolated from dog aortas. Binding reached steady state in 4 minutes at 25° C and was completely reversible. At saturation the total num ... Cite

α Adrenergic receptors in rat parotid cells. I. Correlation of [3H] dihydroergocryptine binding and catecholamine stimulated potassium efflux

Journal Article Journal of Biological Chemistry · December 1, 1977 α-Adrenergic stimulation of parotid acinar cells elicits a release of intracellular K+. The binding of [3H]dihydroergocryptine was used to characterize the α-adrenergic receptor binding sites in both parotid membranes and dissociated parotid acinar cells. ... Cite

α Adrenergic receptors in rat parotid cells. II. Desensitization of receptor binding sites and potassium release

Journal Article Journal of Biological Chemistry · December 1, 1977 Preincubation of dissociated rat parotid acinar cells with the α-adrenergic agonist epinephrine produced a time- and concentration-dependent decrement in the α-adrenergic response of the cells, K+ release. This receptor desensitization by epinephrine was s ... Cite

Regulation of rabbit myometrial alpha adrenergic receptors by estrogen and progesterone.

Journal Article J Clin Invest · October 1977 The effects of estrogen and progesterone on uterine alpha-adrenergic receptors were investigated by direct receptor-binding studies. Immature female rabbits were primed with estrogen by intramuscular injections for 4 days. Other rabbits were primed with pr ... Full text Link to item Cite

Elevated beta-adrenergic receptor number after chronic propranolol treatment.

Journal Article Biochem Biophys Res Commun · September 23, 1977 Full text Link to item Cite

[3H]dihydroergocryptine binding in rat brain.

Journal Article Brain Res · August 26, 1977 [3H]dihydroergocryptine (DHE) appears to bind to alpha-adrenergic receptor sites in rabbit uterine membranes. We have characterized the binding of [3H]DHE to membranes prepared from rat cerebral cortex. alpha-Adrenergic agents were less potent and dopamine ... Full text Link to item Cite

Structure and biological activity of (-)-[3H]dihydroalprenolol, a radioligand for studies of beta-adrenergic receptors.

Journal Article J Med Chem · August 1977 (-)-Alprenolol is a potent competitive beta-adrenergic antagonist. "(-)-[3H]Alprenolol", a radioactive form of this agent produced by catalytic reduction with tritium, has recently been used successfully as a radioligand for direct studies of beta-adrenerg ... Full text Link to item Cite

Thyroid hormone regulation of beta-adrenergic receptor number.

Journal Article J Biol Chem · April 25, 1977 The effects of exogenous thyroid hormones (thyroxine and triiodothyronine) on beta-adrenergic receptors in the rat myocardium were investigated. The potent beta-adrenergic antagonist, (-)-[3H]dihydroalprenolol, was used to directly estimate the number and ... Link to item Cite

Specific receptor sites for chemotactic peptides on human polymorphonuclear leukocytes.

Journal Article Proc Natl Acad Sci U S A · March 1977 Synthetic N-formylmethionyl peptides are chemotactic attractants for human polymorphonuclear leukocytes. The well-defined structure-activity relationship of these peptides in eliciting a chemotactic response suggests that the interaction of the peptides wi ... Full text Link to item Cite

Catecholamine binding to the beta-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · February 1977 The adenylate cyclase-coupled beta-adrenergic receptors of frog erythrocyte membranes have been identified by direct radioligand binding techniques using the potent catecholamine agonist (+/-)[3H]hydroxybenzylisproterenol (2-[3, 4-dihydroxyphenyl]-2-hydrox ... Full text Link to item Cite

Ectopic beta-adrenergic receptor binding sites. possible molecular basis of aberrant catecholamine responsiveness of an adrenocortical tumor adenylate cyclase.

Journal Article J Clin Invest · February 1977 The molecular basis for the aberrant catecholamine responsiveness of the adenylate cyclase of adrenocortical carcinoma 494 was explored. The adenylate cyclase of this corticosteroid-producing, transplanted, adrenal cancer of the rat was stimulated not only ... Full text Link to item Cite

Resolution of beta-adrenergic receptor binding and adenylate cyclase activity by gel exclusion chromatography.

Journal Article J Biol Chem · January 25, 1977 The frog erythrocyte membrane provides an excellent model system for the study of beta-adrenergic receptor-adenylate cyclase interactions since it possesses an adenylate cyclase enzyme which is very responsive to catecholamines. The purpose of these studie ... Link to item Cite

Biochemical mechanisms for regulation of β adrenergic receptors by β adrenergic agonists

Journal Article EXCERPTA MEDICA,AMSTERDAM,ICS · 1977 Incubation of intact frog erythrocytes or purified frog erythrocytes plasma membranes with β-adrenergic agonists leads to a decreased number of functionally active β-adrenergic receptors which may be expressed as a desensitized or refractory state of adeny ... Cite

Separation of β-adrenergic receptors (βAR) from adenylate cyclase (AC)

Journal Article Federation Proceedings · January 1, 1977 Cite

Decreased beta-adrenergic receptor binding in lymphocytes from patients with bronchial asthma

Journal Article American Review of Respiratory Disease · January 1, 1977 Cite

Biochemical mechanisms for regulation of β adrenergic receptors by β adrenergic agonists

Book · January 1, 1977 Incubation of intact frog erythrocytes or purified frog erythrocytes plasma membranes with β-adrenergic agonists leads to a decreased number of functionally active β-adrenergic receptors which may be expressed as a desensitized or refractory state of adeny ... Cite

Identification of alpha-adrenergic receptors in uterine smooth muscle membranes by [3H]dihydroergocryptine binding.

Journal Article J Biol Chem · November 25, 1976 [3H]Dihydroergocryptine, a potent alpha-adrenergic antagonist, was used to label smooth muscle membrane binding sites which have the characteristics expected of alpha-adrenergic receptors. Binding of [3H]dihydroergocryptine to rabbit uterine membranes was ... Link to item Cite

Pharmacological activity of nitroxide analogues of dichloroisoproterenol and propranolol.

Journal Article J Med Chem · October 1976 Spin-labeled analogues of dichloroisoproterenol and propranolol were synthesized. It was found that the KD's of both probes for the beta-adrenergic receptors of frog erythrocytes were about 30-fold higher than the KD's previously reported for the parent an ... Full text Link to item Cite

Biological activity of agarose-immobilized catecholamines.

Journal Article Biochim Biophys Acta · September 24, 1976 Catecholamines substituted to agarose were synthesized in various ways. Norepinephrine and isoproterenol were linked to p-aminobenzamidohexyl agarose by an azo linkage to the catechol ring. Norepinephrine was also couple to hexyl agaros via the amino group ... Full text Link to item Cite

Editorial: Smoking, catecholamines, and the heart.

Journal Article N Engl J Med · September 9, 1976 Full text Link to item Cite

Negative cooperativity among beta-adrenergic receptors in frog erythrocyte membranes.

Journal Article J Biol Chem · August 25, 1976 (-)-[3H]Dihydroalprenolol, a potent competitive beta-adrenergic antagonist, has been previously documented to bind to the adenylate cyclase-coupled beta-adrenergic receptor sites in mammalian and non-mammalian tissues. Steady state binding of (-)-[3H]dihyd ... Link to item Cite

Regulation of beta-adrenergic receptors by guanyl-5'-yl imidodiphosphate and other purine nucleotides.

Journal Article J Biol Chem · August 10, 1976 Guanyl-5'-yl imidodiphosphate (Gpp(NH)p), GTP, and other purine nucleotides selectively decrease the binding affinity of the beta-adrenergic receptors of frog erythrocyte membranes for beta-adrenergic agonists but not antagonists. Shifts in binding affinit ... Link to item Cite

Regulation of adenylate cyclase coupled beta-adrenergic receptors by beta-adrenergic catecholamines.

Journal Article Endocrinology · August 1976 Injection of frogs with beta-adrenergic catecholamines produced a selective desensitization (loss of responsiveness) of the erythrocyte membrane adenylate cylase to subsequent stimulation in vitro by isoproterenol. Basal, prostaglandin E1- and fluoride-sen ... Full text Link to item Cite

Adipocyte beta-adrenergic receptors. Identification and subcellular localization by (-)-[3H]dihydroalprenolol binding.

Journal Article J Biol Chem · May 25, 1976 (--)-[3H]Dihydroalprenolol, a potent beta-adrenergic antagonist, was used to identify binding sites which have the characteristics of beta-adrenergic receptors in membranes from rat adipocytes. The subcellular distribution of the (--)-[3H]Dihydroalprenolol ... Link to item Cite

Alpha-adrenergic receptor identification by (3H)dihydroergocryptine binding.

Journal Article Science · May 21, 1976 A radioactively labeled alpha-adrenergic antagonist, [3H]dihydroergocryptine, binds specifically to a site on rabbit uterine membranes. Binding is rapid, reaching equilibrium in less than 17 minutes at 25 degrees C. Adrenergic agonists compete for this bin ... Full text Link to item Cite

Desensitization of beta-adrenergic receptors by beta-adrenergic agonists in a cell-free system: resensitization by guanosine 5'-(beta, gamma-imino)triphosphate and other purine nucleotides.

Journal Article Proc Natl Acad Sci U S A · May 1976 Incubation of purified frog erythrocyte membranes with beta-adrenergic agonists at 25 degrees produces relatively rapid (half-time about 10 min) desensitization (inactivation) of about 60% of the beta-adrenergic receptor binding sites. The desensitized rec ... Full text Link to item Cite

Solubilization and characterization of the beta-adrenergic receptor binding sites of frog erythrocytes.

Journal Article J Biol Chem · April 25, 1976 Specific beta-adrenergic receptors present in membrane preparations of frog erythrocytes were identified by binding of (-)-[3H]dihydroalprenolol, a potent competitive beta-adrenergic antagonist. The (-)-[3H]dihydroalprenolol binding sites could be solubili ... Link to item Cite

The beta-adrenergic receptor and adenylate cyclase.

Journal Article Biochim Biophys Acta · April 13, 1976 Full text Link to item Cite

Pineal beta adrenergic receptor: correlation of binding of 3H-l-alprenolol with stimulation of adenylate cyclase.

Journal Article J Pharmacol Exp Ther · March 1976 3H-l-Alprenolol, a potent competitive beta adrenergic antagonist, binds to sites in rat pineal gland membranes. The properties of these binding sites were compared to those of the receptors which mediate the beta adrenergic activation of pineal adenylate c ... Link to item Cite

The beta-adrenergic receptor.

Journal Article Life Sci · March 1, 1976 Full text Link to item Cite

Identification of beta-adrenergic receptors in human lymphocytes by (-) (3H) alprenolol binding.

Journal Article J Clin Invest · January 1976 Human lymphocytes are known to posessess a catecholamine-responsive adenylate cyclase which has typical beta-adrenergic specificity. To identify directly and to quantitate these beta-adenergic receptors in human lymphocytes, (-) [3H] alprenolol, a potent b ... Full text Open Access Link to item Cite

NEGATIVE COOPERATIVITY AMONG BETA-ADRENERGIC RECEPTORS (BETA-AR)

Journal Article FEDERATION PROCEEDINGS · January 1, 1976 Link to item Cite

Subsensitivity of adenylate cyclase and decreased beta-adrenergic receptor binding after chronic exposure to (minus)-isoproterenol in vitro.

Journal Article J Biol Chem · July 25, 1975 In vitro incubation of frog erythrocytes with (minus)-isoproterenol, 0.1 mM, at 23 degrees for 10 to 24 hours caused a 63% decline (rho less than 0.001) in the maximum (minus)-isoproterenol-stimulated adenylate cyclase activity in the erythrocyte membranes ... Link to item Cite

Identification of adenylate cyclase-coupled beta-adrenergic receptors in frog erythrocytes with (minus)-[3-H] alprenolol.

Journal Article J Biol Chem · July 10, 1975 (minus)-Alprenolol, a potent, competitive beta-adrenergic antagonist labeled to high specific activity with tritium (17 Ci per mmol), has been used to identify binding sites in frog erythrocyte membranes having many of the characteristics to be expected of ... Link to item Cite

Characteristics of 5'-guanylyl imidodiphosphate-activated adenylate cyclase.

Journal Article J Biol Chem · June 25, 1975 Characteristics of adenylate cyclase stimulation by the GTP analog 5'-guanyl imidodiphosphate Gpp(NH)p have been examined in intact frog erythrocytes, frog erythrocyte membranes, and solubilized canine myocardial preparations. Gpp(NH)p caused marked enzyme ... Link to item Cite

Beta-adrenergic receptors: evidence for negative cooperativity.

Journal Article Biochem Biophys Res Commun · June 16, 1975 Full text Link to item Cite

Catecholamine-induced subsensitivity of adenylate cyclase associated with loss of beta-adrenergic receptor binding sites.

Journal Article Proc Natl Acad Sci U S A · May 1975 Injection of frogs with beta-adrenergic catecholamines for 1-24 hr produces marked subsensitivity of the erythrocyte membrane adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1.] to in vitro stimulation by isoproterenol. The subsensitizatio ... Full text Link to item Cite

Identification of cardiac beta-adrenergic receptors by (minus) [3H]alprenolol binding.

Journal Article Proc Natl Acad Sci U S A · April 1975 (Minus) [3-H] alprenolol, a potent beta-adrenergic antagonist, was used to identify binding sites in a fraction of canine cyocardium. Beta adrenergic agonists and antagonists compete for these binding sites in a manner which directly parallels their known ... Full text Link to item Cite

Guanosine triphosphate binding sites in solubilized myocardium. Relation to adenylate cyclase activity.

Journal Article J Biol Chem · February 10, 1975 Binding of (3H)GTP to solubilized preparations of myocardial adenylate cyclase, partially purified by DEAE-cellulose chromatography, as been studied in an attempt to gain further insight into the mechanisms by which guanine nucleotides regulate adenylate c ... Link to item Cite

Myocardial guanylate cyclase: properties of the enzyme and effects of cholinergic agonists in vitro.

Journal Article Biochim Biophys Acta · January 23, 1975 The characteristics of myocardial guanylate cyclase (GTP pyrophosphatelyase, EC 4.6.1.2) were studied. Specific activity of the myocardial enzyme in five vertebrate species was guinea pig greater than man greater than cat greater than dog greater than rat. ... Full text Link to item Cite

Guanosine triphosphate binding sites in solubilized myocardium. Relation to adenylate cyclase activity

Journal Article Journal of Biological Chemistry · January 1, 1975 Binding of [3H]GTP (guanosine triphosphate) to solubilized preparations of myocardial adenylate cyclase, partially purified by DEAE cellulose chromatography, was studied in an attempt to gain further insight into the mechanisms by which guanine nucleotides ... Cite

(3H)norepinephrine binding and lipolysis by isolated fat cells.

Journal Article Biochim Biophys Acta · December 24, 1974 Full text Link to item Cite

Surface interaction of [3H]norepinephrine with cultured chick embryo myocardial cells

Journal Article BBA - Biomembranes · February 15, 1974 Cultured chick embryo cardiac myoblasts specifically bind [3H]nonrepinephrine. The binding is rapid and reversible. Bound [3H]nonrepinephrine, dissociated by 1 M HCl, can be rebound to fresh cells. β-Adrenergic catecholamines were most potent in displacing ... Full text Cite

3H norepinephrine binding and lipolysis by isolated fat cells

Journal Article Federation Proceedings · January 1, 1974 Cite

β Adrenergic 'isoreceptors', adenylate cyclase (AC) and the heart

Journal Article Circulation · January 1, 1974 Cite

3H norepinephrine binding and lipolysis by isolated fat cells

Journal Article Federation Proceedings · 1974 Cite

Toward isolation of a β adrenergic binding protein

Journal Article Biochemical Pharmacology · January 1, 1974 Cite

[3H] Propranolol binding sites in myocardial membranes: nonidentity with beta adrenergic receptors

Journal Article Molecular Pharmacology · 1974 [3H]Propranolol binds rapidly and reversibly to sites in membranes prepared from canine ventricular myocardium. Two orders of sites were identified. The higher order sites have a value (equilibrium constant) of 4.57 x 104 M-1 and a binding capacity of 3.2 ... Cite

[3H]Norepinephrine binding: Unrelated to catechol-o-methyl transferase

Journal Article Biochemical and Biophysical Research Communications · 1974 [3H]norepinephrine binds in vitro to microsomal membranes derived from a wide variety of tissues. Controversy exists as to the physiological significance of this binding phenomenon and recently the suggestion has been made that this represents binding to t ... Cite

Insulin activity: The solid matrix

Journal Article Science · December 1, 1973 Cite

Letter: Insulin activity: the solid matrix.

Journal Article Science · October 26, 1973 Full text Link to item Cite

Technical problems with agarose-hormone linkage.

Journal Article N Engl J Med · September 27, 1973 Full text Link to item Cite

Identification of the cardiac beta-adrenergic receptor protein: solubilization and purification by affinity chromatography.

Journal Article Proc Natl Acad Sci U S A · October 1972 A protein that binds catecholamines with a specificity parallel to that of their in vivo effects on cardiac contractility (isoproterenol > epinephrine or norepinephrine > dopamine > dihydroxyphenylalanine) was solubilized from a microsomal fraction of cani ... Full text Link to item Cite

A fraction of the ventricular myocardium that has the specificity of the cardiac beta-adrenergic receptor.

Journal Article Proc Natl Acad Sci U S A · August 1971 The 78,000 x g microsomal fraction of canine ventricular myocardium effected a 20-fold concentration of [(3)H]norepinephrine from a 10(-9) M solution. The [(3)H]norepinephrine bound was displaced by physiologic concentrations of the beta-adrenergic catecho ... Full text Link to item Cite

Radioreceptor assay of adrenocorticotropic hormone: new approach to assay of polypeptide hormones in plasma.

Journal Article Science · November 6, 1970 Biologically active iodine-125-labeled adrenocorticotropic hormone (ACTH) binds specifically to ACTH receptors extracted from adrenals. Unlabeled ACTH at 1 picogram per milliliter significantly displaces labeled ACTH from these receptors. This system, whic ... Full text Link to item Cite

ACTH receptors in the adrenal: specific binding of ACTH-125I and its relation to adenyl cyclase.

Journal Article Proc Natl Acad Sci U S A · March 1970 Pure monoiodo ACTH-(125)I was prepared that was biologically active and free of unlabeled ACTH. Extracts of adrenal cortex that contained ACTH-sensitive adenyl cyclase, bound ACTH-(125)I; extracts that lacked the ACTH-sensitive cyclase did not bind ACTH-(1 ... Full text Link to item Cite