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Sci. Signal., 24 April 2012
Vol. 5, Issue 221, p. ra33
[DOI: 10.1126/scisignal.2002522]


Differential β-Arrestin–Dependent Conformational Signaling and Cellular Responses Revealed by Angiotensin Analogs

Brandon Zimmerman1,2*, Alexandre Beautrait3*, Benjamin Aguila1, Ricardo Charles4, Emanuel Escher5, Audrey Claing4, Michel Bouvier3{dagger}, and Stéphane A. Laporte1,2{dagger}

1 McGill University Health Center Research Institute, Department of Medicine, McGill University, Montreal, Quebec H3A 2B2, Canada.
2 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
3 Département de Biochimie and Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
4 Département de Pharmacologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
5 Département de Pharmacologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.

* These authors contributed equally to this work.

Abstract: The angiotensin type 1 receptor (AT1R) and its octapeptide ligand, angiotensin II (AngII), engage multiple downstream signaling pathways, including those mediated by heterotrimeric guanosine triphosphate–binding proteins (G proteins) and those mediated by β-arrestin. Here, we examined AT1R-mediated Gαq and β-arrestin signaling with multiple AngII analogs bearing substitutions at position 8, which is critical for binding to the AT1R and its activation of G proteins. Using assays that discriminated between ligand-promoted recruitment of β-arrestin to the AT1R and its resulting conformational rearrangement, we extend the concept of biased signaling to include the analog’s propensity to differentially promote conformational changes in β-arrestin, two responses that were differentially affected by distinct G protein–coupled receptor kinases. The efficacy of AngII analogs in activating extracellular signal–regulated kinases 1 and 2 correlated with the stability of the complexes between β-arrestin and AT1R in endosomes, rather than with the extent of β-arrestin recruitment to the receptor. In vascular smooth muscle cells, the ligand-induced conformational changes in β-arrestin correlated with whether the ligand promoted β-arrestin–dependent migration or proliferation. Our data indicate that biased signaling not only occurs between G protein– and β-arrestin–mediated pathways but also occurred at the level of the AT1R and β-arrestin, such that different AngII analogs selectively engaged distinct β-arrestin conformations, which led to specific signaling events and cell responses.

{dagger} To whom correspondence should be addressed. E-mail: michel.bouvier{at} (M.B.); stephane.laporte{at} (S.A.L.)

Citation: B. Zimmerman, A. Beautrait, B. Aguila, R. Charles, E. Escher, A. Claing, M. Bouvier, S. A. Laporte, Differential β-Arrestin–Dependent Conformational Signaling and Cellular Responses Revealed by Angiotensin Analogs. Sci. Signal. 5, ra33 (2012).

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