Research ArticleGPCR SIGNALING

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

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

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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.

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