Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 100 (20): 11406-11411

Copyright © 2003 by the National Academy of Sciences.


β-Arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors

Mounia Azzi*, Pascale G. Charest*, Stéphane Angers*, Guy Rousseau{dagger}, Trudy Kohout{ddagger}, Michel Bouvier*,§, and Graciela Piñeyro

*Department of Biochemistry, Université de Montréal, Montréal, QC, Canada H3C 3J7; {dagger}Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada HGJ 1C5; {ddagger}Howard Hughes Medical Institute, Duke University Medical Center, Box 3821, Durham, NC 27710; and Département de Psychiatrie, Centre de Recherche Fernand-Seguin, Université de Montréal, Montréal, QC, Canada H1N 3V2

Received for publication November 1, 2002.

Abstract: It is becoming increasingly clear that signaling via G protein-coupled receptors is a diverse phenomenon involving receptor interaction with a variety of signaling partners. Despite this diversity, receptor ligands are commonly classified only according to their ability to modify G protein-dependent signaling. Here we show that β2AR ligands like ICI118551 and propranolol, which are inverse agonists for Gs-stimulated adenylyl cyclase, induce partial agonist responses for the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) 1/2 thus behaving as dual efficacy ligands. ERK1/2 activation by dual efficacy ligands was not affected by ADP-ribosylation of Gαi and could be observed in S49-cyc cells lacking Gαs indicating that, unlike the conventional agonist isoproterenol, these drugs induce ERK1/2 activation in a Gs/i-independent manner. In contrast, this activation was inhibited by a dominant negative mutant of β-arrestin and was abolished in mouse embryonic fibroblasts lacking β-arrestin 1 and 2. The role of β-arrestin was further confirmed by showing that transfection of β-arrestin 2 in these knockout cells restored ICI118551 promoted ERK1/2 activation. ICI118551 and propranolol also promoted β-arrestin recruitment to the receptor. Taken together, these observations suggest that β-arrestin recruitment is not an exclusive property of agonists, and that ligands classically classified as inverse agonists rely exclusively on β-arrestin for their positive signaling activity. This phenomenon is not unique to β2-adrenergic ligands because SR121463B, an inverse agonist on the V2 vasopressin receptor-stimulated adenylyl cyclase, recruited β-arrestin and stimulated ERK1/2. These results point to a multistate model of receptor activation in which ligand-specific conformations are capable of differentially activating distinct signaling partners.

§ To whom correspondence should be addressed. E-mail: michel.bouvier{at}

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved July 22, 2003

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: GPCRs, G protein-coupled receptors; MAPK, mitogen-activated protein kinase; β2AR, β2-adrenergic receptor; AC, adenylyl cyclase; ERK, extracellular-regulated kinase; MEF, mouse embryonic fibroblast; V2R, type 2 vasopressin receptor; HA, hemagglutinin; BRET, bioluminescence resonance energy transfer. KO, knockout; DKO, double KO.

Quantification of Ligand Bias for Clinically Relevant {beta}2-Adrenergic Receptor Ligands: Implications for Drug Taxonomy.
E. T. van der Westhuizen, B. Breton, A. Christopoulos, and M. Bouvier (2014)
Mol. Pharmacol. 85, 492-509
   Abstract »    Full Text »    PDF »
Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct.
J. D. Hoffert, T. Pisitkun, F. Saeed, J. L. Wilson, and M. A. Knepper (2014)
Am J Physiol Renal Physiol 306, 410-421
   Abstract »    Full Text »    PDF »
Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein.
J. Quoyer, J. M. Janz, J. Luo, Y. Ren, S. Armando, V. Lukashova, J. L. Benovic, K. E. Carlson, S. W. Hunt III, and M. Bouvier (2013)
PNAS 110, E5088-E5097
   Abstract »    Full Text »    PDF »
Decoding Signaling and Function of the Orphan G Protein-Coupled Receptor GPR17 with a Small-Molecule Agonist.
S. Hennen, H. Wang, L. Peters, N. Merten, K. Simon, A. Spinrath, S. Blattermann, R. Akkari, R. Schrage, R. Schroder, et al. (2013)
Science Signaling 6, ra93
   Abstract »    Full Text »    PDF »
Differential and competitive regulation of human melanocortin 1 receptor signaling by {beta}-arrestin isoforms.
M. Abrisqueta, C. Herraiz, A. B. Perez Oliva, B. L. Sanchez-Laorden, C. Olivares, C. Jimenez-Cervantes, and J. C. Garcia-Borron (2013)
J. Cell Sci. 126, 3724-3737
   Abstract »    Full Text »    PDF »
Detection of G Protein-selective G Protein-coupled Receptor (GPCR) Conformations in Live Cells.
R. U. Malik, M. Ritt, B. T. DeVree, R. R. Neubig, R. K. Sunahara, and S. Sivaramakrishnan (2013)
J. Biol. Chem. 288, 17167-17178
   Abstract »    Full Text »    PDF »
A G Protein-Biased Ligand at the {mu}-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine.
S. M. DeWire, D. S. Yamashita, D. H. Rominger, G. Liu, C. L. Cowan, T. M. Graczyk, X.-T. Chen, P. M. Pitis, D. Gotchev, C. Yuan, et al. (2013)
J. Pharmacol. Exp. Ther. 344, 708-717
   Abstract »    Full Text »    PDF »
Regulation of {micro}-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance.
J. T. Williams, S. L. Ingram, G. Henderson, C. Chavkin, M. von Zastrow, S. Schulz, T. Koch, C. J. Evans, and M. J. Christie (2013)
Pharmacol. Rev. 65, 223-254
   Abstract »    Full Text »    PDF »
Induction of Cardiac Fibrosis by {beta}-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/{beta}-Arrestin2-dependent Signaling Pathways.
M. Nakaya, S. Chikura, K. Watari, N. Mizuno, K. Mochinaga, S. Mangmool, S. Koyanagi, S. Ohdo, Y. Sato, T. Ide, et al. (2012)
J. Biol. Chem. 287, 35669-35677
   Abstract »    Full Text »    PDF »
Discovery of Regulators of Receptor Internalization with High-Throughput Flow Cytometry.
Y. Wu, P. H. Tapia, G. W. Fisher, P. C. Simons, J. J. Strouse, T. Foutz, A. S. Waggoner, J. Jarvik, and L. A. Sklar (2012)
Mol. Pharmacol. 82, 645-657
   Abstract »    Full Text »    PDF »
Casting a Wider Net: Whole-Cell Assays to Capture Varied and Biased Signaling.
T. Kenakin (2012)
Mol. Pharmacol. 82, 571-574
   Abstract »    Full Text »    PDF »
Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD.
E. Carpentier, L. A. Greenbaum, D. Rochdi, R. Abrol, W. A. Goddard III, D. G. Bichet, and M. Bouvier (2012)
J. Am. Soc. Nephrol. 23, 1635-1640
   Abstract »    Full Text »    PDF »
M. Breitman, S. Kook, L. E. Gimenez, B. N. Lizama, M. C. Palazzo, E. V. Gurevich, and V. V. Gurevich (2012)
J. Biol. Chem. 287, 19653-19664
   Abstract »    Full Text »    PDF »
Differential {beta}-Arrestin-Dependent Conformational Signaling and Cellular Responses Revealed by Angiotensin Analogs.
B. Zimmerman, A. Beautrait, B. Aguila, R. Charles, E. Escher, A. Claing, M. Bouvier, and S. A. Laporte (2012)
Science Signaling 5, ra33
   Abstract »    Full Text »    PDF »
Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy.
R. Rahmeh, M. Damian, M. Cottet, H. Orcel, C. Mendre, T. Durroux, K. S. Sharma, G. Durand, B. Pucci, E. Trinquet, et al. (2012)
PNAS 109, 6733-6738
   Abstract »    Full Text »    PDF »
Differential Association of Receptor-G{beta}{gamma} Complexes with {beta}-Arrestin2 Determines Recycling Bias and Potential for Tolerance of Delta Opioid Receptor Agonists.
N. Audet, I. Charfi, O. Mnie-Filali, M. Amraei, A.-J. Chabot-Dore, M. Millecamps, L. S. Stone, and G. Pineyro (2012)
J. Neurosci. 32, 4827-4840
   Abstract »    Full Text »    PDF »
Fluorescence/Bioluminescence Resonance Energy Transfer Techniques to Study G-Protein-Coupled Receptor Activation and Signaling.
M. J. Lohse, S. Nuber, and C. Hoffmann (2012)
Pharmacol. Rev. 64, 299-336
   Abstract »    Full Text »    PDF »
Functional Selective Oxytocin-derived Agonists Discriminate between Individual G Protein Family Subtypes.
M. Busnelli, A. Sauliere, M. Manning, M. Bouvier, C. Gales, and B. Chini (2012)
J. Biol. Chem. 287, 3617-3629
   Abstract »    Full Text »    PDF »
V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists.
K. Takahashi, N. Makita, K. Manaka, M. Hisano, Y. Akioka, K. Miura, N. Takubo, A. Iida, N. Ueda, M. Hashimoto, et al. (2012)
J. Biol. Chem. 287, 2099-2106
   Abstract »    Full Text »    PDF »
Nuclear GPCRs in cardiomyocytes: an insider's view of {beta}-adrenergic receptor signaling.
G. Vaniotis, B. G. Allen, and T. E. Hebert (2011)
Am J Physiol Heart Circ Physiol 301, H1754-H1764
   Abstract »    Full Text »    PDF »
CXCR7/CXCR4 Heterodimer Constitutively Recruits {beta}-Arrestin to Enhance Cell Migration.
F. M. Decaillot, M. A. Kazmi, Y. Lin, S. Ray-Saha, T. P. Sakmar, and P. Sachdev (2011)
J. Biol. Chem. 286, 32188-32197
   Abstract »    Full Text »    PDF »
Ligand Modulation of the Epstein-Barr Virus-induced Seven-transmembrane Receptor EBI2: IDENTIFICATION OF A POTENT AND EFFICACIOUS INVERSE AGONIST.
T. Benned-Jensen, C. Smethurst, P. J. Holst, K. R. Page, H. Sauls, B. Sivertsen, T. W. Schwartz, A. Blanchard, R. Jepras, and M. M. Rosenkilde (2011)
J. Biol. Chem. 286, 29292-29302
   Abstract »    Full Text »    PDF »
Unique Interaction Pattern for a Functionally Biased Ghrelin Receptor Agonist.
B. Sivertsen, M. Lang, T. M. Frimurer, N. D. Holliday, A. Bach, S. Els, M. S. Engelstoft, P. S. Petersen, A. N. Madsen, T. W. Schwartz, et al. (2011)
J. Biol. Chem. 286, 20845-20860
   Abstract »    Full Text »    PDF »
Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of {beta}-arrestin2.
C. Yin, R. Zhang, Y. Xu, Q. Chen, and X. Xie (2011)
Mol. Biol. Cell 22, 1608-1616
   Abstract »    Full Text »    PDF »
Nuclear Factor {kappa}B Downregulates the Transient Outward Potassium Current Ito,f Through Control of KChIP2 Expression.
B. K. Panama, D. Latour-Villamil, G. P. Farman, D. Zhao, S.-S. Bolz, L. A. Kirshenbaum, and P. H. Backx (2011)
Circ. Res. 108, 537-543
   Abstract »    Full Text »    PDF »
Functional Selectivity and Biased Receptor Signaling.
T. Kenakin (2011)
J. Pharmacol. Exp. Ther. 336, 296-302
   Abstract »    Full Text »    PDF »
Serine 363 of the {delta}-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands.
C. Xu, M.-H. Hong, L.-S. Zhang, Y.-Y. Hou, Y.-H. Wang, F.-F. Wang, Y.-J. Chen, X.-J. Xu, J. Chen, X. Xie, et al. (2010)
J. Cell Sci. 123, 4259-4270
   Abstract »    Full Text »    PDF »
{beta}-Blocker drugs mediate calcium signaling in native central nervous system neurons by {beta}-arrestin-biased agonism.
A. V. Tzingounis, M. von Zastrow, and G. A. Yudowski (2010)
PNAS 107, 21028-21033
   Abstract »    Full Text »    PDF »
Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes.
N. J. Smith and G. Milligan (2010)
Pharmacol. Rev. 62, 701-725
   Abstract »    Full Text »    PDF »
Differential Signaling of the Endogenous Agonists at the {beta}2-Adrenergic Receptor.
S. Reiner, M. Ambrosio, C. Hoffmann, and M. J. Lohse (2010)
J. Biol. Chem. 285, 36188-36198
   Abstract »    Full Text »    PDF »
Energy Landscapes as a Tool to Integrate GPCR Structure, Dynamics, and Function.
X. Deupi and B. K. Kobilka (2010)
Physiology 25, 293-303
   Abstract »    Full Text »    PDF »
Protein-protein interactions monitored in cells from transgenic mice using bioluminescence resonance energy transfer.
M. Audet, M. Lagace, D. W. Silversides, and M. Bouvier (2010)
FASEB J 24, 2829-2838
   Abstract »    Full Text »    PDF »
{beta}-Arrestin-Biased Agonism of the Angiotensin Receptor Induced by Mechanical Stress.
K. Rakesh, B. Yoo, I.-M. Kim, N. Salazar, K.-S. Kim, and H. A. Rockman (2010)
Science Signaling 3, ra46
   Abstract »    Full Text »    PDF »
Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery.
T. Kenakin and L. J. Miller (2010)
Pharmacol. Rev. 62, 265-304
   Abstract »    Full Text »    PDF »
Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling.
L. M. Luttrell, D. Gesty-Palmer, and D. R. Sibley (2010)
Pharmacol. Rev. 62, 305-330
   Abstract »    Full Text »    PDF »
Morphine-like Opiates Selectively Antagonize Receptor-Arrestin Interactions.
P. Molinari, V. Vezzi, M. Sbraccia, C. Gro, D. Riitano, C. Ambrosio, I. Casella, and T. Costa (2010)
J. Biol. Chem. 285, 12522-12535
   Abstract »    Full Text »    PDF »
The Constitutive Activity of the Human Muscarinic M3 Receptor Unmasks Differences in the Pharmacology of Anticholinergics.
P. Casarosa, T. Kiechle, P. Sieger, M. Pieper, and F. Gantner (2010)
J. Pharmacol. Exp. Ther. 333, 201-209
   Abstract »    Full Text »    PDF »
Ligand- and Heterodimer-Directed Signaling of the CB1 Cannabinoid Receptor.
B. D. Hudson, T. E. Hebert, and M. E. M. Kelly (2010)
Mol. Pharmacol. 77, 1-9
   Abstract »    Full Text »    PDF »
Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus.
F. Jean-Alphonse, S. Perkovska, M.-C. Frantz, T. Durroux, C. Mejean, D. Morin, S. Loison, D. Bonnet, M. Hibert, B. Mouillac, et al. (2009)
J. Am. Soc. Nephrol. 20, 2190-2203
   Abstract »    Full Text »    PDF »
Activation of Intracellular Signaling Pathways by the Murine Cytomegalovirus G Protein-Coupled Receptor M33 Occurs via PLC-{beta}/PKC-Dependent and -Independent Mechanisms.
J. D. Sherrill, M. P. Stropes, O. D. Schneider, D. E. Koch, F. M. Bittencourt, J. L. C. Miller, and W. E. Miller (2009)
J. Virol. 83, 8141-8152
   Abstract »    Full Text »    PDF »
The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex.
X. J. Yao, G. Velez Ruiz, M. R. Whorton, S. G. F. Rasmussen, B. T. DeVree, X. Deupi, R. K. Sunahara, and B. Kobilka (2009)
PNAS 106, 9501-9506
   Abstract »    Full Text »    PDF »
Evidence for Distinct Antagonist-Revealed Functional States of 5-Hydroxytryptamine2A Receptor Homodimers.
J. Brea, M. Castro, J. Giraldo, J. F. Lopez-Gimenez, J. F. Padin, F. Quintian, M. I. Cadavid, M. T. Vilaro, G. Mengod, K. A. Berg, et al. (2009)
Mol. Pharmacol. 75, 1380-1391
   Abstract »    Full Text »    PDF »
Hematopoietic Protein Tyrosine Phosphatase Mediates {beta}2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes.
J. W. McAlees and V. M. Sanders (2009)
Mol. Cell. Biol. 29, 675-686
   Abstract »    Full Text »    PDF »
The C-terminal Tail of CRTH2 Is a Key Molecular Determinant That Constrains G{alpha}i and Downstream Signaling Cascade Activation.
R. Schroder, N. Merten, J. M. Mathiesen, L. Martini, A. Kruljac-Letunic, F. Krop, A. Blaukat, Y. Fang, E. Tran, T. Ulven, et al. (2009)
J. Biol. Chem. 284, 1324-1336
   Abstract »    Full Text »    PDF »
M. Sato, D. S. Hutchinson, B. A. Evans, and R. J. Summers (2008)
Mol. Pharmacol. 74, 1417-1428
   Abstract »    Full Text »    PDF »
Physical Interaction of Calmodulin with the 5-Hydroxytryptamine2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling.
M. Labasque, E. Reiter, C. Becamel, J. Bockaert, and P. Marin (2008)
Mol. Biol. Cell 19, 4640-4650
   Abstract »    Full Text »    PDF »
Site-specific Cleavage of G Protein-coupled Receptor-engaged {beta}-Arrestin: INFLUENCE OF THE AT1 RECEPTOR CONFORMATION ON SCISSILE SITE SELECTION.
C. Lee, S. Bhatt, A. Shukla, R. W. Desnoyer, S. P. Yadav, M. Kim, S.-H. Jang, and S. S. Karnik (2008)
J. Biol. Chem. 283, 21612-21620
   Abstract »    Full Text »    PDF »
Distinct conformational changes in {beta}-arrestin report biased agonism at seven-transmembrane receptors.
A. K. Shukla, J. D. Violin, E. J. Whalen, D. Gesty-Palmer, S. K. Shenoy, and R. J. Lefkowitz (2008)
PNAS 105, 9988-9993
   Abstract »    Full Text »    PDF »
Agonist-selective signaling is determined by the receptor location within the membrane domains.
H. Zheng, J. Chu, Y. Qiu, H. H. Loh, and P.-Y. Law (2008)
PNAS 105, 9421-9426
   Abstract »    Full Text »    PDF »
Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing {delta}-Opioid Receptors and Heterotrimeric G Proteins.
N. Audet, C. Gales, E. Archer-Lahlou, M. Vallieres, P. W. Schiller, M. Bouvier, and G. Pineyro (2008)
J. Biol. Chem. 283, 15078-15088
   Abstract »    Full Text »    PDF »
Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells.
Y. Cordeaux, S. J. Briddon, S. P. H. Alexander, B. Kellam, and S. J. Hill (2008)
FASEB J 22, 850-860
   Abstract »    Full Text »    PDF »
{beta}-Arrestin-biased Agonism at the {beta}2-Adrenergic Receptor.
M. T. Drake, J. D. Violin, E. J. Whalen, J. W. Wisler, S. K. Shenoy, and R. J. Lefkowitz (2008)
J. Biol. Chem. 283, 5669-5676
   Abstract »    Full Text »    PDF »
Role of -Arrestin-mediated Desensitization and Signaling in the Control of Angiotensin AT1a Receptor-stimulated Transcription.
M.-H. Lee, H. M. El-Shewy, D. K. Luttrell, and L. M. Luttrell (2008)
J. Biol. Chem. 283, 2088-2097
   Abstract »    Full Text »    PDF »
Norepinephrine- and Epinephrine-induced Distinct 2-Adrenoceptor Signaling Is Dictated by GRK2 Phosphorylation in Cardiomyocytes.
Y. Wang, V. De Arcangelis, X. Gao, B. Ramani, Y.-s. Jung, and Y. Xiang (2008)
J. Biol. Chem. 283, 1799-1807
   Abstract »    Full Text »    PDF »
-Arrestin-Dependent {micro}-Opioid Receptor-Activated Extracellular Signal-Regulated Kinases (ERKs) Translocate to Nucleus in Contrast to G Protein-Dependent ERK Activation.
H. Zheng, H. H. Loh, and P.-Y. Law (2008)
Mol. Pharmacol. 73, 178-190
   Abstract »    Full Text »    PDF »
Functional Selectivity through Protean and Biased Agonism: Who Steers the Ship?.
T. Kenakin (2007)
Mol. Pharmacol. 72, 1393-1401
   Abstract »    Full Text »    PDF »
Ligand-Directed Signaling at the beta3-Adrenoceptor Produced by 3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) Relative to Receptor Agonists.
M. Sato, T. Horinouchi, D. S. Hutchinson, B. A. Evans, and R. J. Summers (2007)
Mol. Pharmacol. 72, 1359-1368
   Abstract »    Full Text »    PDF »
Quantification of dynamic protein complexes using Renilla luciferase fragment complementation applied to protein kinase A activities in vivo.
E. Stefan, S. Aquin, N. Berger, C. R. Landry, B. Nyfeler, M. Bouvier, and S. W. Michnick (2007)
PNAS 104, 16916-16921
   Abstract »    Full Text »    PDF »
A unique mechanism of beta-blocker action: Carvedilol stimulates beta-arrestin signaling.
J. W. Wisler, S. M. DeWire, E. J. Whalen, J. D. Violin, M. T. Drake, S. Ahn, S. K. Shenoy, and R. J. Lefkowitz (2007)
PNAS 104, 16657-16662
   Abstract »    Full Text »    PDF »
Receptor heterodimerization leads to a switch in signaling: {beta}-arrestin2-mediated ERK activation by {micro}-{delta} opioid receptor heterodimers.
R. Rozenfeld and L. A. Devi (2007)
FASEB J 21, 2455-2465
   Abstract »    Full Text »    PDF »
G-protein-coupled receptor expression, function, and signaling in macrophages.
J. Lattin, D. A. Zidar, K. Schroder, S. Kellie, D. A. Hume, and M. J. Sweet (2007)
J. Leukoc. Biol. 82, 16-32
   Abstract »    Full Text »    PDF »
Structure and Conformational Changes in the C-terminal Domain of the beta2-Adrenoceptor: INSIGHTS FROM FLUORESCENCE RESONANCE ENERGY TRANSFER STUDIES.
S. Granier, S. Kim, A. M. Shafer, V. R. P. Ratnala, J. J. Fung, R. N. Zare, and B. Kobilka (2007)
J. Biol. Chem. 282, 13895-13905
   Abstract »    Full Text »    PDF »
Missing Links: Mechanisms of Protean Agonism.
R. R. Neubig (2007)
Mol. Pharmacol. 71, 1200-1202
   Abstract »    Full Text »    PDF »
Protean Agonism at the Dopamine D2 Receptor: (S)-3-(3-Hydroxyphenyl)-N-propylpiperidine Is an Agonist for Activation of Go1 but an Antagonist/Inverse Agonist for Gi1,Gi2, and Gi3.
J. R. Lane, B. Powney, A. Wise, S. Rees, and G. Milligan (2007)
Mol. Pharmacol. 71, 1349-1359
   Abstract »    Full Text »    PDF »
An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations.
N. Makita, J. Sato, K. Manaka, Y. Shoji, A. Oishi, M. Hashimoto, T. Fujita, and T. Iiri (2007)
PNAS 104, 5443-5448
   Abstract »    Full Text »    PDF »
Bioluminescence Resonance Energy Transfer as a Screening Assay: Focus on Partial and Inverse Agonism.
L. Elster, C. Elling, and A. Heding (2007)
J Biomol Screen 12, 41-49
   Abstract »    PDF »
Proline-rich Motifs in the Parathyroid Hormone (PTH)/PTH-related Protein Receptor C Terminus Mediate Scaffolding of c-Src with beta-Arrestin2 for ERK1/2 Activation.
A. Rey, D. Manen, R. Rizzoli, J. Caverzasio, and S. L. Ferrari (2006)
J. Biol. Chem. 281, 38181-38188
   Abstract »    Full Text »    PDF »
The Natural Inverse Agonist Agouti-related Protein Induces Arrestin-mediated Endocytosis of Melanocortin-3 and -4 Receptors.
A. Breit, K. Wolff, H. Kalwa, H. Jarry, T. Buch, and T. Gudermann (2006)
J. Biol. Chem. 281, 37447-37456
   Abstract »    Full Text »    PDF »
Activation of STAT3 by G{alpha}s Distinctively Requires Protein Kinase A, JNK, and Phosphatidylinositol 3-Kinase.
A. M. F. Liu, R. K. H. Lo, C. S. S. Wong, C. Morris, H. Wise, and Y. H. Wong (2006)
J. Biol. Chem. 281, 35812-35825
   Abstract »    Full Text »    PDF »
Distinct Signaling Profiles of beta1 and beta2 Adrenergic Receptor Ligands toward Adenylyl Cyclase and Mitogen-Activated Protein Kinase Reveals the Pluridimensionality of Efficacy.
S. Galandrin and M. Bouvier (2006)
Mol. Pharmacol. 70, 1575-1584
   Abstract »    Full Text »    PDF »
beta-Arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.
K. Rajagopal, E. J. Whalen, J. D. Violin, J. A. Stiber, P. B. Rosenberg, R. T. Premont, T. M. Coffman, H. A. Rockman, and R. J. Lefkowitz (2006)
PNAS 103, 16284-16289
   Abstract »    Full Text »    PDF »
G protein-coupled receptor kinase 2 and {beta}-arrestins are recruited to FSH receptor in stimulated rat primary Sertoli cells.
S. Marion, E. Kara, P. Crepieux, V. Piketty, N. Martinat, F. Guillou, and E. Reiter (2006)
J. Endocrinol. 190, 341-350
   Abstract »    Full Text »    PDF »
G-protein-coupled Receptor Kinase Specificity for beta-Arrestin Recruitment to the beta2-Adrenergic Receptor Revealed by Fluorescence Resonance Energy Transfer.
J. D. Violin, X.-R. Ren, and R. J. Lefkowitz (2006)
J. Biol. Chem. 281, 20577-20588
   Abstract »    Full Text »    PDF »
Constitutive ERK1/2 Activation by a Chimeric Neurokinin 1 Receptor-beta-Arrestin1 Fusion Protein: PROBING THE COMPOSITION AND FUNCTION OF THE G PROTEIN-COUPLED RECEPTOR "SIGNALSOME".
F. Jafri, H. M. El-Shewy, M.-H. Lee, M. Kelly, D. K. Luttrell, and L. M. Luttrell (2006)
J. Biol. Chem. 281, 19346-19357
   Abstract »    Full Text »    PDF »
Heterotrimeric G proteins form stable complexes with adenylyl cyclase and Kir3.1 channels in living cells.
R. V. Rebois, M. Robitaille, C. Gales, D. J. Dupre, A. Baragli, P. Trieu, N. Ethier, M. Bouvier, and T. E. Hebert (2006)
J. Cell Sci. 119, 2807-2818
   Abstract »    Full Text »    PDF »
Distinct beta-Arrestin- and G Protein-dependent Pathways for Parathyroid Hormone Receptor-stimulated ERK1/2 Activation.
D. Gesty-Palmer, M. Chen, E. Reiter, S. Ahn, C. D. Nelson, S. Wang, A. E. Eckhardt, C. L. Cowan, R. F. Spurney, L. M. Luttrell, et al. (2006)
J. Biol. Chem. 281, 10856-10864
   Abstract »    Full Text »    PDF »
Evidence for a Secondary State of the Human {beta}3-Adrenoceptor.
J. G. Baker (2005)
Mol. Pharmacol. 68, 1645-1655
   Abstract »    Full Text »    PDF »
Characterization of Isoprenaline- and Salmeterol-Stimulated Interactions between {beta}2-Adrenoceptors and {beta}-Arrestin 2 Using {beta}-Galactosidase Complementation in C2C12 Cells.
A. A. Carter and S. J. Hill (2005)
J. Pharmacol. Exp. Ther. 315, 839-848
   Abstract »    Full Text »    PDF »
Seven-Transmembrane Receptor Signaling Through {beta}-Arrestin.
S. K. Shenoy and R. J. Lefkowitz (2005)
Sci. STKE 2005, cm10
   Abstract »    Full Text »    PDF »
{beta}-Arrestin 2 Expression Determines the Transcriptional Response to Lysophosphatidic Acid Stimulation in Murine Embryo Fibroblasts.
D. Gesty-Palmer, H. E. Shewy, T. A. Kohout, and L. M. Luttrell (2005)
J. Biol. Chem. 280, 32157-32167
   Abstract »    Full Text »    PDF »
The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling.
S. Maudsley, B. Martin, and L. M. Luttrell (2005)
J. Pharmacol. Exp. Ther. 314, 485-494
   Abstract »    Full Text »    PDF »
Identification of Indole Derivatives Exclusively Interfering with a G Protein-Independent Signaling Pathway of the Prostaglandin D2 Receptor CRTH2.
J. M. Mathiesen, T. Ulven, L. Martini, L. O. Gerlach, A. Heinemann, and E. Kostenis (2005)
Mol. Pharmacol. 68, 393-402
   Abstract »    Full Text »    PDF »
Probing the {beta}2 Adrenoceptor Binding Site with Catechol Reveals Differences in Binding and Activation by Agonists and Partial Agonists.
G. Swaminath, X. Deupi, T. W. Lee, W. Zhu, F. S. Thian, T. S. Kobilka, and B. Kobilka (2005)
J. Biol. Chem. 280, 22165-22171
   Abstract »    Full Text »    PDF »
Multiple Signaling States of G-Protein-Coupled Receptors.
D. M. Perez and S. S. Karnik (2005)
Pharmacol. Rev. 57, 147-161
   Abstract »    Full Text »    PDF »
Mutation of the DRY Motif Reveals Different Structural Requirements for the CC Chemokine Receptor 5-Mediated Signaling and Receptor Endocytosis.
B. Lagane, S. Ballet, T. Planchenault, K. Balabanian, E. Le Poul, C. Blanpain, Y. Percherancier, I. Staropoli, G. Vassart, M. Oppermann, et al. (2005)
Mol. Pharmacol. 67, 1966-1976
   Abstract »    Full Text »    PDF »
Transduction of Receptor Signals by {beta}-Arrestins.
R. J. Lefkowitz and S. K. Shenoy (2005)
Science 308, 512-517
   Abstract »    Full Text »    PDF »
The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a "Biased Agonist" Mechanism.
A. Reversi, V. Rimoldi, T. Marrocco, P. Cassoni, G. Bussolati, M. Parenti, and B. Chini (2005)
J. Biol. Chem. 280, 16311-16318
   Abstract »    Full Text »    PDF »
The Natural Mutation Encoding a C Terminus-Truncated 5-Hydroxytryptamine2B Receptor Is a Gain of Proliferative Functions.
M. Deraet, P. Manivet, A. Janoshazi, J. Callebert, S. Guenther, L. Drouet, J.-M. Launay, and L. Maroteaux (2005)
Mol. Pharmacol. 67, 983-991
   Abstract »    Full Text »    PDF »
Internalization and Src Activity Regulate the Time Course of ERK Activation by Delta Opioid Receptor Ligands.
N. Audet, M. Paquin-Gobeil, O. Landry-Paquet, P. W. Schiller, and G. Pineyro (2005)
J. Biol. Chem. 280, 7808-7816
   Abstract »    Full Text »    PDF »
Different G protein-coupled receptor kinases govern G protein and {beta}-arrestin-mediated signaling of V2 vasopressin receptor.
X.-R. Ren, E. Reiter, S. Ahn, J. Kim, W. Chen, and R. J. Lefkowitz (2005)
PNAS 102, 1448-1453
   Abstract »    Full Text »    PDF »
Reciprocal Regulation of Agonist and Inverse Agonist Signaling Efficacy upon Short-Term Treatment of the Human {delta}-Opioid Receptor with an Inverse Agonist.
G. Pineyro, M. Azzi, A. deLean, P. W. Schiller, and M. Bouvier (2005)
Mol. Pharmacol. 67, 336-348
   Abstract »    Full Text »    PDF »
Receptor activity-independent recruitment of {beta}arrestin2 reveals specific signalling modes.
S. Terrillon and M. Bouvier (2004)
EMBO J. 23, 3950-3961
   Abstract »    Full Text »    PDF »
Differential Desensitization, Receptor Phosphorylation, {beta}-Arrestin Recruitment, and ERK1/2 Activation by the Two Endogenous Ligands for the CC Chemokine Receptor 7.
T. A. Kohout, S. L. Nicholas, S. J. Perry, G. Reinhart, S. Junger, and R. S. Struthers (2004)
J. Biol. Chem. 279, 23214-23222
   Abstract »    Full Text »    PDF »
Agonist Binding: A Multistep Process.
B. Kobilka (2004)
Mol. Pharmacol. 65, 1060-1062
   Full Text »
Inverse Agonists: Tools to Reveal Ligand-Specific Conformations of G Protein-Coupled Receptors.
P. L. Prather (2004)
Sci. STKE 2004, pe1
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882