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, Trudy Kohout, Michel Bouvier, Graciela Piñeyro

Research output: Contribution to journalArticle

384 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)11406-11411
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number20
DOIs
StatePublished - Sep 30 2003
Externally publishedYes

Fingerprint

Arrestin
G-Protein-Coupled Receptors
Ligands
Adenylyl Cyclases
Propranolol
Vasopressin Receptors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Isoproterenol
GTP-Binding Proteins
Adrenergic Agents
Adenosine Diphosphate
Transfection
Fibroblasts
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

β-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. / Azzi, Mounia; Charest, Pascale G; Angers, Stéphane; Rousseau, Guy; Kohout, Trudy; Bouvier, Michel; Piñeyro, Graciela.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 20, 30.09.2003, p. 11406-11411.

Research output: Contribution to journalArticle

Azzi, Mounia ; Charest, Pascale G ; Angers, Stéphane ; Rousseau, Guy ; Kohout, Trudy ; Bouvier, Michel ; Piñeyro, Graciela. / β-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 20. pp. 11406-11411.
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