Scholars@Duke
Seungkirl Ahn

Seungkirl Ahn

Associate Professor in Medicine
Medicine, Cardiology
seungkirl.ahn@duke.edu
Duke Box 3821, Durham, NC 27710
467 CARL Bldg, Durham, NC 27710

Selected Publications

A positive allosteric modulator of the β1AR with antagonist activity for catecholaminergic polymorphic ventricular tachycardia.

Journal Article J Clin Invest · December 15, 2025 Orthosteric beta blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by adverse effects such as fatigu ... 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

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

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

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

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

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

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

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

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

Design, synthesis, and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the β2-adrenergic receptor.

Journal Article Bioorg Med Chem · May 15, 2018 The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis ... Full text Link to item 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

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

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

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

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

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

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

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

Synthesis of β2-AR agonist BI-167107

Journal Article Chinese Journal of Organic Chemistry · March 1, 2013 BI-167107 is a new long-acting β2-adrenergic receptor (β2-AR) agonist, and has important application in determining the critical structures of receptor/ligand proteins complex of G-protein-coupled receptor (GPCR). By employing 2-nitro ... Full text 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

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

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

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

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

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-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}-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

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

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

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

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

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

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

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

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

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

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

Regulation of epidermal growth factor receptor internalization by G protein-coupled receptors.

Journal Article Biochemistry · March 18, 2003 The epidermal growth factor (EGF) receptor (EGFR) plays a central role in regulating cell proliferation, differentiation, and migration. Cellular responses to EGF are dependent upon the amount of EGFR present on the cell surface. Stimulation with EGF induc ... 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

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

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

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

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

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

Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells.

Journal Article Curr Biol · March 12, 1998 Although phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is a well-characterized precursor for the second messengers inositol 1,4,5-trisphosphate, diacylglycerol [1] and phosphatidylinositol 3,4,5-trisphosphate [2], it also interacts with the actin-b ... 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