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Lawrence Simeon Barak

Associate Research Professor of Cell Biology
Cell Biology
Duke Box 3287, Durham, NC 27710
483 Clin & Res Labs, Durham, NC 27710

Selected Publications


Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens.

Journal Article Neuropharmacology · August 15, 2023 Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. ... Full text Link to item Cite

Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.

Journal Article Biochemistry · April 4, 2023 The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-indep ... Full text Link to item Cite

Prenatal heroin exposure alters brain morphology and connectivity in adolescent mice.

Journal Article NMR Biomed · February 2023 The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long-lasting effects on health and wellbeing. Effects on t ... Full text Link to item Cite

Ghrelin receptor signaling in health and disease: a biased view.

Journal Article Trends Endocrinol Metab · February 2023 As allosteric complexes, G-protein-coupled receptors (GPCRs) respond to extracellular stimuli and pleiotropically couple to intracellular transducers to elicit signaling pathway-dependent effects in a process known as biased signaling or functional selecti ... Full text Link to item Cite

Establishment of multi-stage intravenous self-administration paradigms in mice.

Journal Article Scientific reports · December 2022 Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opioid addiction in animals, but technical limitat ... Full text Cite

Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

Journal Article Proc Natl Acad Sci U S A · March 8, 2022 SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through dist ... Full text Link to item Cite

HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.

Journal Article Mol Cancer Res · October 2021 HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the in ... Full text Link to item Cite

Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.

Journal Article Trends Pharmacol Sci · April 2021 G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in the genome and the most successful family of targets of FDA-approved drugs. New frontiers in GPCR drug discovery remain, however, as achieving receptor subtype selectivi ... Full text Link to item Cite

PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.

Journal Article Nat Commun · November 19, 2020 The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, ps ... Full text Link to item Cite

β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.

Journal Article Cell · June 11, 2020 Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their seve ... Full text Link to item Cite

A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Journal Article Nat Commun · December 2, 2019 Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unk ... Full text Link to item Cite

Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators.

Journal Article J Med Chem · September 12, 2019 Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite exten ... Full text Link to item Cite

Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.

Journal Article ACS Pharmacol Transl Sci · August 9, 2019 G-protein-coupled receptors (GPCRs) can bias signaling through distinct biochemical pathways that originate from G-protein/receptor and β-arrestin/receptor complexes. Receptor conformations supporting β-arrestin engagement depend on multiple receptor deter ... Full text Link to item Cite

A Brief History of the β-Arrestins.

Journal Article Methods Mol Biol · 2019 Arrestins have now been implicated in the actions of virtually every G protein-coupled receptor (GPCR) for which they have been examined. Originally discovered for their role in the turnoff of visual perception, their newly discovered pleotropic functions ... Full text Link to item Cite

Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires βarrestin-2.

Journal Article Synapse · January 2018 The "brain-gut" peptide ghrelin, which mediates food-seeking behaviors, is recognized as a very strong endogenous modulator of dopamine (DA) signaling. Ghrelin binds the G protein-coupled receptor GHSR1a, and administration of ghrelin increases the rewardi ... Full text Link to item Cite

Design, synthesis and biological evaluation of GPR55 agonists.

Journal Article Bioorg Med Chem · August 15, 2017 GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and phar ... Full text Link to item Cite

Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin.

Journal Article FASEB J · June 2017 Apelin signaling plays an important role during embryo development and regulates angiogenesis, cardiovascular activity, and energy metabolism in adulthood. Overexpression and hyperactivity of this signaling pathway is observed in various pathologic states, ... Full text Link to item Cite

Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled receptor-5 diminishes cell fitness.

Journal Article J Biol Chem · April 28, 2017 The leucine-rich G protein-coupled receptor-5 (LGR5) is expressed in adult tissue stem cells of many epithelia, and its overexpression is negatively correlated with cancer prognosis. LGR5 potentiates WNT/β-catenin signaling through its unique constitutive ... Full text Link to item Cite

Probing the Allosteric Role of the α5 Subunit of α3β4α5 Nicotinic Acetylcholine Receptors by Functionally Selective Modulators and Ligands.

Journal Article ACS Chem Biol · March 17, 2017 Nicotinic acetylcholine receptors regulate the nicotine dependence encountered with cigarette smoking, and this has stimulated a search for drugs binding the responsible receptor subtypes. Studies link a gene cluster encoding for α3β4α5-D398N nicotinic ace ... Full text Link to item Cite

Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.

Journal Article Bioorg Med Chem · March 15, 2017 The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin ... Full text Link to item Cite

Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens.

Journal Article Neuropharmacology · August 15, 2023 Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. ... Full text Link to item Cite

Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator.

Journal Article Biochemistry · April 4, 2023 The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-indep ... Full text Link to item Cite

Prenatal heroin exposure alters brain morphology and connectivity in adolescent mice.

Journal Article NMR Biomed · February 2023 The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long-lasting effects on health and wellbeing. Effects on t ... Full text Link to item Cite

Ghrelin receptor signaling in health and disease: a biased view.

Journal Article Trends Endocrinol Metab · February 2023 As allosteric complexes, G-protein-coupled receptors (GPCRs) respond to extracellular stimuli and pleiotropically couple to intracellular transducers to elicit signaling pathway-dependent effects in a process known as biased signaling or functional selecti ... Full text Link to item Cite

Establishment of multi-stage intravenous self-administration paradigms in mice.

Journal Article Scientific reports · December 2022 Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opioid addiction in animals, but technical limitat ... Full text Cite

Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

Journal Article Proc Natl Acad Sci U S A · March 8, 2022 SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through dist ... Full text Link to item Cite

HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.

Journal Article Mol Cancer Res · October 2021 HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the in ... Full text Link to item Cite

Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.

Journal Article Trends Pharmacol Sci · April 2021 G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in the genome and the most successful family of targets of FDA-approved drugs. New frontiers in GPCR drug discovery remain, however, as achieving receptor subtype selectivi ... Full text Link to item Cite

PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.

Journal Article Nat Commun · November 19, 2020 The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, ps ... Full text Link to item Cite

β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.

Journal Article Cell · June 11, 2020 Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their seve ... Full text Link to item Cite

A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Journal Article Nat Commun · December 2, 2019 Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unk ... Full text Link to item Cite

Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators.

Journal Article J Med Chem · September 12, 2019 Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite exten ... Full text Link to item Cite

Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.

Journal Article ACS Pharmacol Transl Sci · August 9, 2019 G-protein-coupled receptors (GPCRs) can bias signaling through distinct biochemical pathways that originate from G-protein/receptor and β-arrestin/receptor complexes. Receptor conformations supporting β-arrestin engagement depend on multiple receptor deter ... Full text Link to item Cite

A Brief History of the β-Arrestins.

Journal Article Methods Mol Biol · 2019 Arrestins have now been implicated in the actions of virtually every G protein-coupled receptor (GPCR) for which they have been examined. Originally discovered for their role in the turnoff of visual perception, their newly discovered pleotropic functions ... Full text Link to item Cite

Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires βarrestin-2.

Journal Article Synapse · January 2018 The "brain-gut" peptide ghrelin, which mediates food-seeking behaviors, is recognized as a very strong endogenous modulator of dopamine (DA) signaling. Ghrelin binds the G protein-coupled receptor GHSR1a, and administration of ghrelin increases the rewardi ... Full text Link to item Cite

Design, synthesis and biological evaluation of GPR55 agonists.

Journal Article Bioorg Med Chem · August 15, 2017 GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and phar ... Full text Link to item Cite

Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin.

Journal Article FASEB J · June 2017 Apelin signaling plays an important role during embryo development and regulates angiogenesis, cardiovascular activity, and energy metabolism in adulthood. Overexpression and hyperactivity of this signaling pathway is observed in various pathologic states, ... Full text Link to item Cite

Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled receptor-5 diminishes cell fitness.

Journal Article J Biol Chem · April 28, 2017 The leucine-rich G protein-coupled receptor-5 (LGR5) is expressed in adult tissue stem cells of many epithelia, and its overexpression is negatively correlated with cancer prognosis. LGR5 potentiates WNT/β-catenin signaling through its unique constitutive ... Full text Link to item Cite

Probing the Allosteric Role of the α5 Subunit of α3β4α5 Nicotinic Acetylcholine Receptors by Functionally Selective Modulators and Ligands.

Journal Article ACS Chem Biol · March 17, 2017 Nicotinic acetylcholine receptors regulate the nicotine dependence encountered with cigarette smoking, and this has stimulated a search for drugs binding the responsible receptor subtypes. Studies link a gene cluster encoding for α3β4α5-D398N nicotinic ace ... Full text Link to item Cite

Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.

Journal Article Bioorg Med Chem · March 15, 2017 The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin ... Full text Link to item Cite

ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse.

Journal Article ACS Chem Biol · July 15, 2016 Pharmacological treatment for methamphetamine addiction will provide important societal benefits. Neurotensin receptor NTR1 and dopamine receptor distributions coincide in brain areas regulating methamphetamine-associated reward, and neurotensin peptides p ... Full text Link to item Cite

Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones.

Journal Article Bioorg Med Chem Lett · April 1, 2016 A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly ... Full text Link to item Cite

A rapid and affordable screening platform for membrane protein trafficking.

Journal Article BMC Biol · December 17, 2015 BACKGROUND: Membrane proteins regulate a diversity of physiological processes and are the most successful class of targets in drug discovery. However, the number of targets adequately explored in chemical space and the limited resources available for scree ... Full text Link to item Cite

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

Journal Article Breast Cancer Res · December 2015 Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kina ... Full text Link to item Cite

Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.

Journal Article Bioorg Med Chem · September 1, 2015 The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approve ... Full text Link to item Cite

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions.

Journal Article J Cell Sci · March 15, 2015 Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism f ... Full text Link to item Cite

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

Journal Article Breast Cancer Res · February 15, 2015 INTRODUCTION: Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 ... Full text Link to item Cite

Phenotypic regulation of the sphingosine 1-phosphate receptor miles apart by G protein-coupled receptor kinase 2.

Journal Article Biochemistry · January 27, 2015 The evolutionarily conserved DRY motif at the end of the third helix of rhodopsin-like, class-A G protein-coupled receptors (GPCRs) is a major regulator of receptor stability, signaling activity, and β-arrestin-mediated internalization. Substitution of the ... Full text Link to item Cite

G Protein and β-arrestin signaling bias at the ghrelin receptor.

Journal Article J Biol Chem · November 28, 2014 The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, a ... Full text Link to item Cite

IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells.

Journal Article Proc Natl Acad Sci U S A · September 2, 2014 The pseudostratified airway epithelium of the lung contains a balanced proportion of multiciliated and secretory luminal cells that are maintained and regenerated by a population of basal stem cells. However, little is known about how these processes are m ... Full text Link to item Cite

Imidazole-derived agonists for the neurotensin 1 receptor.

Journal Article Bioorg Med Chem Lett · January 1, 2014 A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior ... Full text Link to item Cite

Identification of the GPR55 antagonist binding site using a novel set of high-potency GPR55 selective ligands.

Journal Article Biochemistry · December 31, 2013 GPR55 is a class A G protein-coupled receptor (GPCR) that has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Initially deorphanized as a cannabinoid receptor, GPR55 has been shown to be activated b ... Full text Link to item Cite

Triphenylmethane dye activation of beta-arrestin.

Journal Article Biochemistry · August 13, 2013 β-Arrestins regulate G protein-coupled receptor signaling as competitive inhibitors and protein adaptors. Low molecular weight biased ligands that bind receptors and discriminate between the G protein dependent arm and β-arrestin, clathrin-associated arm o ... Full text Link to item Cite

Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor.

Journal Article ACS Med Chem Lett · July 20, 2013 The neurotensin 1 receptor (NTR1) is an important therapeutic target for a range of disease states including addiction. A high throughput screening campaign, followed by medicinal chemistry optimization, led to the discovery of a non-peptidic β-arrestin bi ... Full text Link to item Cite

Novel adamantyl cannabinoids as CB1 receptor probes.

Journal Article J Med Chem · May 23, 2013 In previous studies, compound 1 (AM411), a 3-(1-adamantyl) analogue of the phytocannabinoid (-)-Δ(8)-tetrahydrocannabinol (Δ(8)-THC), was shown to have improved affinity and selectivity for the CB1 receptor. In this work, we further explored the role of th ... Full text Link to item Cite

Abstract 5681: Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives.

Conference Cancer Research · April 15, 2013 AbstractThe Wnt signal transduction pathway is dysregulated in many cancers, including colorectal cancer (CRC) where activating mutations in this pathway occur in over 80% of sporadic colorectal cancers. As ... Full text Cite

Constitutive internalization of the leucine-rich G protein-coupled receptor-5 (LGR5) to the trans-Golgi network.

Journal Article J Biol Chem · April 12, 2013 LGR5 is a Wnt pathway associated G protein-coupled receptor (GPCR) that serves as a molecular determinant of stem cells in numerous tissues including the intestine, stomach, hair follicle, eye, and mammary gland. Despite its importance as a marker for this ... Full text Link to item Cite

The intestinal glucose-apelin cycle controls carbohydrate absorption in mice.

Journal Article Gastroenterology · April 2013 BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is p ... Full text Link to item Cite

Small molecule modulators of Wnt/β-catenin signaling.

Journal Article Bioorg Med Chem Lett · April 1, 2013 The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer. Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery. Recently, w ... Full text Link to item Cite

The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to β-arrestin-2 recruitment.

Journal Article PLoS One · 2013 Lgr5 is a membrane protein related to G protein-coupled receptors (GPCR)s whose expression identifies stem cells in multiple tissues and is strongly correlated with cancer. Despite the recent identification of endogenous ligands for Lgr5, its mode of signa ... Full text Link to item Cite

Regulation of hedgehog signaling by Myc-interacting zinc finger protein 1, Miz1.

Journal Article PLoS One · 2013 Smoothened (Smo) mediated Hedgehog (Hh) signaling plays an essential role in regulating embryonic development and postnatal tissue homeostasis. Aberrant activation of the Hh pathway contributes to the formation and progression of various cancers. In verteb ... Full text Link to item Cite

Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling.

Journal Article Bioorg Med Chem · November 15, 2012 The Hedgehog signaling pathway plays an essential role in embryo development and adult tissue homeostasis, in regulating stem cells and is abnormally activated in many cancers. Given the importance of this signaling pathway, we developed a novel and versat ... Full text Link to item Cite

The insecticide synergist piperonyl butoxide inhibits hedgehog signaling: assessing chemical risks.

Journal Article Toxicol Sci · August 2012 The spread of chemicals, including insecticides, into the environment often raises public health concerns, as exemplified by a recent epidemiologic study associating in utero piperonyl butoxide (PBO) exposure with delayed mental development. The insecticid ... Full text Link to item Cite

Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells.

Journal Article Breast Cancer Res · June 7, 2012 INTRODUCTION: Sustained HER2 signaling at the cell surface is an oncogenic mechanism in a significant proportion of breast cancers. While clinically effective therapies targeting HER2 such as mAbs and tyrosine kinase inhibitors exist, tumors overexpressing ... Full text Link to item Cite

Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy.

Journal Article ACS Chem Neurosci · March 21, 2012 Herein we present the outcome of a high throughput screening (HTS) campaign-based strategy for the rapid identification and optimization of selective and general chemotypes for both kappa (κ) opioid receptor (KOR) activation and inhibition. In this program ... Full text Link to item Cite

Modeling of bias for the analysis of receptor signaling in biochemical systems.

Journal Article Biochemistry · February 14, 2012 Ligand bias is a recently introduced concept in the receptor signaling field that underlies innovative strategies for targeted drug design. Ligands, as a consequence of conformational selectivity, produce signaling bias in which some downstream biochemical ... Full text Link to item Cite

BRET biosensors to study GPCR biology, pharmacology, and signal transduction.

Journal Article Front Endocrinol (Lausanne) · 2012 Bioluminescence resonance energy transfer (BRET)-based biosensors have been extensively used over the last decade to study protein-protein interactions and intracellular signal transduction in living cells. In this review, we discuss the various BRET biose ... Full text Link to item Cite

Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor.

Journal Article Mol Pharmacol · September 2011 The ability of dopamine receptors to interact with other receptor subtypes may provide mechanisms for modulating dopamine-related functions and behaviors. In particular, there is evidence suggesting that the trace amine-associated receptor 1 (TAAR1) affect ... Full text Link to item Cite

Visualizing receptor endocytosis and trafficking.

Journal Article Methods Mol Biol · 2011 G-protein-coupled 7 transmembrane domain receptors (GPCR-7TMR) represent the largest class of membrane protein drug targets. They respond to a plethora of ligands ranging from small molecules to polypeptide hormones. Upon activation, almost all GPCR-7TMRs ... Full text Link to item Cite

Glucocorticoid hedgehog agonists in neurogenesis.

Journal Article Vitam Horm · 2011 The process of neurogenesis in mammals, which is prolific and widespread at birth, gradually slows with aging and in humans becomes restricted to areas including the cerebellum and hippocampus. It has been reported that exposure to glucocorticoids can impa ... Full text Link to item Cite

The dopamine metabolite 3-methoxytyramine is a neuromodulator.

Journal Article PLoS One · October 18, 2010 Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce be ... Full text Open Access Link to item Cite

Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity.

Journal Article Mol Pharmacol · October 2010 Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, dimi ... Full text Link to item Cite

Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach.

Journal Article Am J Physiol Gastrointest Liver Physiol · August 2010 Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying s ... Full text Link to item Cite

Identification of select glucocorticoids as Smoothened agonists: potential utility for regenerative medicine.

Journal Article Proc Natl Acad Sci U S A · May 18, 2010 Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development o ... Full text Open Access Link to item Cite

The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling.

Journal Article Biochemistry · November 3, 2009 Wnt proteins bind to seven-transmembrane Frizzled receptors to mediate the important developmental, morphogenetic, and stem cell related tissue-regenerative effects of Wnt signaling. Dysregulated Wnt signaling is associated with many cancers. Currently, th ... Full text Link to item Cite

Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands.

Journal Article J Biol Chem · October 23, 2009 The cannabinoid receptor 1 (CB(1)) and CB(2) cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR ... Full text Link to item Cite

Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase.

Journal Article Mol Biol Cell · December 2008 Smoothened, a heptahelical membrane protein, functions as the transducer of Hedgehog signaling. The kinases that modulate Smoothened have been thoroughly analyzed in flies. However, little is known about how phosphorylation affects Smoothened in vertebrate ... 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

Regulation of M2-type pyruvate kinase mediated by the high-affinity IgE receptors is required for mast cell degranulation.

Journal Article Br J Pharmacol · July 2008 BACKGROUND AND PURPOSE: M2-type pyruvate kinase (M2PK) was found to interact directly with the 'ITAM' region of the gamma chain of the high-affinity IgE receptor (FcvarepsilonRI). Our hypothesis was that mast cell degranulation might require the Fcvarepsil ... 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

N-terminal tyrosine modulation of the endocytic adaptor function of the beta-arrestins.

Journal Article J Biol Chem · June 29, 2007 The highly homologous beta-arrestin1 and -2 adaptor proteins play important roles in the function of G protein-coupled receptors. Either beta-arrestin variant can function as a molecular chaperone for clathrin-mediated receptor internalization. This role d ... Full text Link to item Cite

A beta-arrestin binding determinant common to the second intracellular loops of rhodopsin family G protein-coupled receptors.

Journal Article J Biol Chem · February 3, 2006 beta-Arrestins have been shown to inhibit competitively G protein-dependent signaling and to mediate endocytosis for many of the hundreds of nonvisual rhodopsin family G protein-coupled receptors (GPCR). An open question of fundamental importance concernin ... Full text Link to item Cite

Relationship between the G protein signaling and homologous desensitization of G protein-coupled receptors.

Journal Article Biochem Biophys Res Commun · January 13, 2006 Signaling and desensitization of G protein-coupled receptor are intimately related, and measuring them separately requires certain parameters that represent desensitization independently of signaling. In this study, we tested whether desensitization requir ... Full text Link to item Cite

Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

Journal Article PLoS Biol · August 2005 Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine ... Full text Link to item Cite

G protein-coupled receptor kinase regulates dopamine D3 receptor signaling by modulating the stability of a receptor-filamin-beta-arrestin complex. A case of autoreceptor regulation.

Journal Article J Biol Chem · April 1, 2005 In addition to its postsynaptic role, the dopamine D3 receptor (D3R) serves as a presynaptic autoreceptor, where it provides continuous feedback regulation of dopamine release at nerve terminals for processes as diverse as emotional tone and locomotion. D3 ... Full text Link to item Cite

Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway.

Journal Article Science · December 24, 2004 beta-arrestins are multifunctional proteins that act as scaffolds and transducers of intracellular signals from heptahelical transmembrane-spanning receptors (7TMR). Hedgehog (Hh) signaling, which uses the putative 7TMR, Smoothened, is established as a fun ... 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

Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signaling and interaction with the Na(+)/H(+) exchanger regulatory factor.

Journal Article J Biol Chem · October 1, 2004 G protein-coupled receptor kinase-2 (GRK2) can phosphorylate and desensitize the platelet-derived growth factor receptor-beta (PDGFRbeta) in heterologous cellular systems. To determine whether GRK2 regulates the PDGFRbeta in physiologic systems, we examine ... 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

Identification of Drosophila neuropeptide receptors by G protein-coupled receptors-beta-arrestin2 interactions.

Journal Article J Biol Chem · December 26, 2003 Activation of G protein-coupled receptors (GPCR) leads to the recruitment of beta-arrestins. By tagging the beta-arrestin molecule with a green fluorescent protein, we can visualize the activation of GPCRs in living cells. We have used this approach to de- ... Full text Link to item Cite

The G protein-coupled receptor GPR4 suppresses ERK activation in a ligand-independent manner.

Journal Article Biochemistry · October 28, 2003 The lysophospholipids, lysophosphatidic acid, sphingosine-1-phosphate, and sphingosylphosphorylcholine (SPC), are bioactive lipid molecules that regulate diverse biological processes. Although the specific G protein-coupled receptors for lysophosphatidic a ... 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

G protein-coupled receptor desensitization as a measure of signaling: modeling of arrestin recruitment to activated CCK-B receptors.

Journal Article Assay Drug Dev Technol · June 2003 Gastrin is one of the principle hormonal mediators of gastric acid secretion, and its cognate receptor (CCK-B) is a member of the superfamily of GPCRs. Patients with hypergastrinemia may present with a variety of symptoms, including gastric ulcers or malig ... Full text Link to item Cite

Constitutive desensitization: a new paradigm for g protein-coupled receptor regulation.

Journal Article Assay Drug Dev Technol · April 2003 GPCRs are a large family of cell-surface proteins that regulate many important biochemical pathways and physiological responses. The isolation and characterization of GPCRs represent one of the more remarkable success stories that occurred during the revol ... Full text Link to item Cite

Role of the cytoplasmic tails of CXCR1 and CXCR2 in mediating leukocyte migration, activation, and regulation.

Journal Article J Immunol · March 15, 2003 IL-8 (or CXCL8) activates the receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB) to induce chemotaxis in leukocytes, but only CXCR1 mediates cytotoxic and cross-regulatory signals. This may be due to the rapid internalization of CXCR2. To investigate the roles of ... Full text Link to item Cite

Human substance P receptor lacking the C-terminal domain remains competent to desensitize and internalize.

Journal Article J Neurochem · February 2003 Substance P receptor (SPR) and its naturally occurring splice-variant, lacking the C-terminal tail, are found in brain and spinal cord. Whether C-terminally truncated SPR desensitizes like full-length SPR is controversial. We used a multivaried approach to ... Full text Link to item Cite

Apparent loss-of-function mutant GPCRs revealed as constitutively desensitized receptors.

Journal Article Biochemistry · October 8, 2002 Featured Publication The DRY motif is a triplet amino acid sequence (aspartic acid, arginine, and tyrosine) that is highly conserved in G protein-coupled receptors (GPCRs). Recently, we have shown that a molecular determinant for nephrogenic diabetes insipidus, the vasopressin ... Full text Link to item Cite

Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex.

Journal Article J Cell Biol · August 5, 2002 Internalization of beta-adrenergic receptors (betaARs) occurs by the sequential binding of beta-arrestin, the clathrin adaptor AP-2, and clathrin. D-3 phosphoinositides, generated by the action of phosphoinositide 3-kinase (PI3K) may regulate the endocytic ... Full text Link to item Cite

Regulation of arrestin-3 phosphorylation by casein kinase II.

Journal Article J Biol Chem · May 10, 2002 Featured Publication Arrestins play an important role in regulating the function of G protein-coupled receptors including receptor desensitization, internalization, down-regulation, and signaling via nonreceptor tyrosine kinases and mitogen-activated protein kinases. Previous ... Full text Link to item Cite

Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins.

Journal Article J Biol Chem · October 5, 2001 Featured Publication The D(2) and D(3) receptors (D(2)R and D(3)R), which are potential targets for antipsychotic drugs, have a similar structural architecture and signaling pathway. Furthermore, in some brain regions they are expressed in the same cells, suggesting that diffe ... Full text Link to item Cite

Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*.

Journal Article J Biol Chem · June 1, 2001 Featured Publication beta-Arrestins bind agonist-activated G protein-coupled receptors (GPCRs) and mediate their desensitization and internalization. Although beta-arrestins dissociate from some receptors at the plasma membrane, such as the beta2 adrenergic receptor, they rema ... Full text Link to item Cite

Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration.

Journal Article J Biol Chem · June 1, 2001 Featured Publication Agonist-dependent desensitization of the beta-adrenergic receptor requires translocation and activation of the beta-adrenergic receptor kinase1 by liberated Gbetagamma subunits. Subsequent internalization of agonist-occupied receptors occurs as a result of ... Full text Link to item Cite

Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility.

Journal Article Science · March 2, 2001 Featured Publication EDG-1 is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP). Cell migration toward platelet-derived growth factor (PDGF), which stimulates sphingosine kinase and increases intracellular SPP, was de ... Full text Link to item Cite

Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus.

Journal Article Proc Natl Acad Sci U S A · January 2, 2001 Featured Publication Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalize ... Full text Link to item Cite

The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits.

Journal Article J Biol Chem · July 28, 2000 Beta-arrestins are cytosolic proteins that regulate the signaling and the internalization of G protein-coupled receptors (GPCRs). Although termination of receptor coupling requires beta-arrestin binding to agonist-activated receptors, GPCR endocytosis invo ... Full text Link to item Cite

Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors.

Journal Article J Biol Chem · June 2, 2000 Visual arrestin, betaarrestin1, and betaarrestin2 comprise a family of intracellular proteins that desensitize G protein-coupled receptors (GPCRs). In addition, betaarrestin1 and betaarrestin2 target desensitized receptors to clathrin-coated pits for endoc ... Full text Link to item Cite

Mutational analysis of Gbetagamma and phospholipid interaction with G protein-coupled receptor kinase 2.

Journal Article J Biol Chem · April 7, 2000 Agonist-dependent regulation of G protein-coupled receptors is dependent on their phosphorylation by G protein-coupled receptor kinases (GRKs). GRK2 and GRK3 are selectively regulated in vitro by free Gbetagamma subunits and negatively charged membrane pho ... Full text Link to item Cite

Dopamine neuronal transport kinetics and effects of amphetamine.

Journal Article J Neurochem · December 1999 The dopamine (DA) transporter (DAT) regulates DA neurotransmission by recycling DA back into neurons. Drugs that interfere with DAT function, e.g., cocaine and amphetamine, can have profound behavioral effects. The kinetics of DA transport by DAT in isolat ... Full text Link to item Cite

Association of beta-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization.

Journal Article J Biol Chem · November 5, 1999 Resensitization of G protein-coupled receptors (GPCRs) following agonist-mediated desensitization is a necessary step for maintaining physiological responsiveness. However, the molecular mechanisms governing the nature of GPCR resensitization are poorly un ... Full text Link to item Cite

Properties of secretin receptor internalization differ from those of the beta(2)-adrenergic receptor.

Journal Article J Biol Chem · October 29, 1999 The endocytic pathway of the secretin receptor, a class II GPCR, is unknown. Some class I G protein-coupled receptors (GPCRs), such as the beta(2)-adrenergic receptor (beta(2)-AR), internalize in clathrin-coated vesicles and this process is mediated by G p ... Full text Link to item Cite

Cellular trafficking of G protein-coupled receptor/beta-arrestin endocytic complexes.

Journal Article J Biol Chem · April 16, 1999 beta-Arrestins are multifunctional proteins identified on the basis of their ability to bind and uncouple G protein-coupled receptors (GPCR) from heterotrimeric G proteins. In addition, beta-arrestins play a central role in mediating GPCR endocytosis, a ke ... Full text Link to item Cite

The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis.

Journal Article Proc Natl Acad Sci U S A · March 30, 1999 betaarrestins mediate the desensitization of the beta2-adrenergic receptor (beta2AR) and many other G protein-coupled receptors (GPCRs). Additionally, betaarrestins initiate the endocytosis of these receptors via clathrin coated-pits and interact directly ... Full text Link to item Cite

Real-time visualization of the cellular redistribution of G protein-coupled receptor kinase 2 and beta-arrestin 2 during homologous desensitization of the substance P receptor.

Journal Article J Biol Chem · March 12, 1999 The substance P receptor (SPR) is a G protein-coupled receptor (GPCR) that plays a key role in pain regulation. The SPR desensitizes in the continued presence of agonist, presumably via mechanisms that implicate G protein-coupled receptor kinases (GRKs) an ... Full text Link to item Cite

Constitutively active alpha-1b adrenergic receptor mutants display different phosphorylation and internalization features.

Journal Article Mol Pharmacol · February 1999 We compared the phosphorylation and internalization properties of constitutively active alpha-1b adrenergic receptor (AR) mutants carrying mutations in two distant receptor domains, i.e., at A293 in the distal part of the third intracellular loop and at D1 ... Full text Link to item Cite

Agonist-specific regulation of delta-opioid receptor trafficking by G protein-coupled receptor kinase and beta-arrestin.

Journal Article J Recept Signal Transduct Res · 1999 Opioid receptors mediate multiple biological functions through their interaction with endogenous opioid peptides as well as opioid alkaloids including morphine and etorphine. Previously we have reported that the ability of distinct opioid agonists to diffe ... Full text Link to item Cite

Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness.

Journal Article Proc Natl Acad Sci U S A · June 9, 1998 The G protein-coupled mu-opioid receptor (mu OR) mediates the physiological effects of endogenous opioid peptides as well as the structurally distinct opioid alkaloids morphine and etorphine. An intriguing feature of mu OR signaling is the differential rec ... 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

Visualization of dynamic trafficking of a protein kinase C betaII/green fluorescent protein conjugate reveals differences in G protein-coupled receptor activation and desensitization.

Journal Article J Biol Chem · April 24, 1998 Protein kinase C (PKC) links various extracellular signals to intracellular responses and is activated by diverse intracellular factors including diacylglycerol, Ca2+, and arachidonic acid. In this study, using a fully functional green fluorescent protein ... 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

Molecular mechanisms of G protein-coupled receptor desensitization and resensitization.

Journal Article Life Sci · 1998 Beta-arrestin proteins play a dual role in regulating G protein-coupled receptor (GPCR) responsiveness by contributing to both receptor desensitization and internalization. Recently, beta-arrestins were also shown to be critical determinants for beta2-adre ... Full text Link to item Cite

A beta-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation.

Journal Article J Biol Chem · October 31, 1997 Featured Publication G protein-coupled receptors (GPCR) represent the single most important drug targets for medical therapy, and information from genome sequencing and genomic data bases has substantially accelerated their discovery. The lack of a systematic approach either t ... Full text Link to item Cite

A central role for beta-arrestins and clathrin-coated vesicle-mediated endocytosis in beta2-adrenergic receptor resensitization. Differential regulation of receptor resensitization in two distinct cell types.

Journal Article J Biol Chem · October 24, 1997 G protein-coupled receptor (GPCR) sequestration to endosomes is proposed to be the mechanism by which G protein-coupled receptor kinase (GRK)-phosphorylated receptors are dephosphorylated and resensitized. The identification of beta-arrestins as GPCR traff ... 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

Internal trafficking and surface mobility of a functionally intact beta2-adrenergic receptor-green fluorescent protein conjugate.

Journal Article Mol Pharmacol · February 1997 The beta2-adrenergic receptor (beta2AR) is prototypic of the large family of G protein-coupled receptors (GPCRs) whose desensitization and resensitization are regulated by intracellular kinases, arrestin proteins, phosphatases, and ill-defined components o ... 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

Pleiotropic role for GRKs and β-arrestins in receptor regulation

Journal Article News in Physiological Sciences · January 1, 1997 G protein-coupled receptor kinases and arrestin proteins are well-characterized mediators of agonist-dependent G protein-coupled receptor desensitization. These proteins are now shown to play a dual role in receptor regulation by mediating both receptor un ... Full text Cite

G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins.

Journal Article Can J Physiol Pharmacol · October 1996 G-protein-coupled receptors (GPCRs) represent a large family of proteins that transduce extracellular signals to the interior of cells. Signalling through these receptors rapidly desensitized primarily as the consequence of receptor phosphorylation, but re ... Full text Link to item Cite

Dynamin and beta-arrestin reveal distinct mechanisms for G protein-coupled receptor internalization.

Journal Article J Biol Chem · August 2, 1996 The process of agonist-promoted internalization (sequestration) of G protein-coupled receptors (GPCRs) is intimately linked to the regulation of GPCR responsiveness. Following agonist-mediated desensitization, sequestration of GPCR is presumably associated ... 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

Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization.

Journal Article Science · January 19, 1996 beta-Arrestins are proteins that bind phosphorylated heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) and contribute to the desensitization of GPCRs by uncoupling the signal transduction process. Resensitization of GPCR responsivene ... Full text Link to item Cite

The conserved seven-transmembrane sequence NP(X)2,3Y of the G-protein-coupled receptor superfamily regulates multiple properties of the beta 2-adrenergic receptor.

Journal Article Biochemistry · November 28, 1995 The beta 2-adrenergic receptor (beta 2AR) is a member of a large superfamily of seven transmembrane domain, G-protein-coupled receptors. Within the putative seventh transmembrane domain of the beta 2AR is a sequence of amino acids, NPLIY, which is conserve ... Full text Link to item Cite

Role of phosphorylation in agonist-promoted beta 2-adrenergic receptor sequestration. Rescue of a sequestration-defective mutant receptor by beta ARK1.

Journal Article J Biol Chem · October 20, 1995 The beta 2-adrenergic receptor (beta 2AR) belongs to the large family of G protein-coupled receptors. Mutation of tyrosine residue 326 to an alanine resulted in a beta 2AR mutant (beta 2AR-Y326A) that was defective in its ability to sequester and was less ... Full text Link to item Cite

Modeling of sequestration and down regulation in cells containing beta2-adrenergic receptors.

Journal Article J Recept Signal Transduct Res · 1995 Desensitization of G-protein coupled receptors following agonist occupancy is accompanied by two temporally distinguishable cellular trafficking phenomena of the receptors referred to as sequestration and down regulation. For the beta2-adrenergic receptor, ... Full text 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

Severe encephalopathy associated with ifosfamide administration in two children with metastatic tumors.

Journal Article J Neurooncol · 1988 We studied two children with recurrent cancer, who during treatment with ifosfamide developed severe encephalopathy characterized by coma of several days duration. Ifosfamide was used as a single drug without mesna as an uroprotector. A 1-hour infusion of ... Full text Link to item Cite

Electric field-induced redistribution and postfield relaxation of low density lipoprotein receptors on cultured human fibroblasts.

Journal Article J Cell Biol · July 1985 The lateral mobility of unliganded low density lipoprotein-receptor (LDL-R) on the surface of human fibroblasts has been investigated by studying the generation and relaxation of concentration differences induced by exposure of the cultured cells to steady ... Full text Link to item Cite

Diffusion of low density lipoprotein-receptor complex on human fibroblasts.

Journal Article J Cell Biol · December 1982 Diffusion of the complex consisting of low density lipoprotein (LDL) bound to its receptor on the surface of human fibroblasts has been measured with the help of an intensely fluorescent, biologically active LDL derivative, dioctadecylindocarbocyanine LDL ... Full text Link to item Cite

Fluorescent low density lipoprotein for observation of dynamics of individual receptor complexes on cultured human fibroblasts.

Journal Article J Cell Biol · September 1981 The visible wavelength excited fluorophore 3,3'-dioctadecylindocarbocyanine iodide (Dil[3]) was incorporated into human low density lipoprotein (LDL) to form the highly fluorescent LDL derivative dil(3)-LDL. Dil(3)-LDL binds to normal human fibroblasts and ... Full text Link to item Cite

F-actin aggregates in transformed cells.

Journal Article J Cell Biol · September 1981 Polymerized actin has been found aggregated into distinctive patches inside transformed cells in culture. The F-actin-specific fluorescent probe, nitrobenzoxadiazole-phallacidin, labels these F-actin aggregates near the ventral cell surface of cells transf ... Full text Link to item Cite

In vivo staining of cytoskeletal actin by autointernalization of nontoxic concentrations of nitrobenzoxadiazole-phallacidin.

Journal Article J Cell Biol · May 1981 The blue light-excited fluorescent phallotoxin derivative nitrobenzoxadiazole phallacidin (NBD-Ph) was used to stain entire tissue culture monolayers of live L6 mouse cells and other mammalian cell lines without the aid of permeabilization treatment. Altho ... Full text Link to item Cite

Differential staining of actin in metaphase spindles with 7-nitrobenz-2-oxa-1,3-diazole-phallacidin and fluorescent DNase: is actin involved in chromosomal movement?

Journal Article Proc Natl Acad Sci U S A · May 1981 The distribution and polymerization state of actin in metaphase rat kangaroo cells was studied by fluorescence microscopy. Formaldehyde-fixed, acetone-extracted cells were labeled with either of two types of actin probes. The first, 7-nitrobenz-2-oxa-1,3-d ... Full text Link to item Cite

Fluorescence studies on modes of cytochalasin B and phallotoxin action on cytoplasmic streaming in Chara.

Journal Article J Cell Biol · February 1981 Various investigations have suggested that cytoplasmic streaming in characean algae is driven by interaction between subcortical actin bundles and endoplasmic myosin. To further test this hypothesis, we have perfused cytotoxic actin-binding drugs and fluor ... Full text Link to item Cite

Molecular mobility on the cell surface.

Journal Article Biochem Soc Symp · 1981 Many measurements of lateral diffusion of proteins and lipids on cell membranes and lipid model membranes have become available through application of fluorescence photobleaching recovery methods. A puzzling aspect of these results is slow diffusion and pa ... Link to item Cite

DIFFUSIBILITY OF CELL-SURFACE PROTEINS-RELEASE OF CONSTRAINTS

Journal Article JOURNAL OF CELL BIOLOGY · January 1, 1981 Link to item Cite

MOLECULAR-MOTION OF INDIVIDUAL LDL MOLECULES ON CELL-MEMBRANES

Journal Article BIOPHYSICAL JOURNAL · January 1, 1981 Link to item Cite

Fluorescence staining of the actin cytoskeleton in living cells with 7-nitrobenz-2-oxa-1,3-diazole-phallacidin.

Journal Article Proc Natl Acad Sci U S A · February 1980 An active fluorescent derivative of the actin-binding mushroom toxin phallacidin has been synthesized. Convenient methods were developed to stain actin cytoskeletal structures in living and fixed cultured animal cells and actively streaming algal cells. Ac ... Full text Link to item Cite

INVIVO LABELING OF CYTOSKELETAL ACTIN BY NBD-PHALLACIDIN

Journal Article JOURNAL OF CELL BIOLOGY · January 1, 1980 Link to item Cite

CORRECTION

Journal Article PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES · January 1, 1980 Link to item Cite

Mobility and distribution of a cell surface glycoprotein and its interaction with other membrane components.

Journal Article Proc Natl Acad Sci U S A · July 1977 Fluorescence photobleaching recovery and immunofluorescence methods have been used to study the lateral mobility and topographical distribution of a major cell surface glycoprotein (CSP). Both endogenous CSP and fluorescent-labeled exogenous CSP bind to th ... Full text Link to item Cite

Lateral diffusion in planar lipid bilayers.

Journal Article Science · January 21, 1977 Direct measurements by fluorescence correlation spectroscopy of lateral diffusion coefficients of fluorescent lipid analogs in lipid bilaryer membranes indicate self-diffusion coefficients D greater than 10(-7) square centimeters per second for various lip ... Full text Link to item Cite