Research ArticleGPCR SIGNALING

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

See allHide authors and affiliations

Sci. Signal.  24 Apr 2012:
Vol. 5, Issue 221, pp. ra33
DOI: 10.1126/scisignal.2002522

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

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.

View Full Text