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PNAS 100 (20): 11406-11411

Copyright © 2003 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

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}umontreal.ca.

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.


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   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 »

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