beta-Arrestin-biased agonism of the angiotensin receptor induced by mechanical stress.

Published online

Journal Article

beta-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is beta-arrestin-biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through beta-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced beta-arrestin-biased signaling downstream of angiotensin II type I receptors (AT1Rs) in the absence of ligand or G protein activation. Mechanical stretch triggered an AT1R-mediated conformational change in beta-arrestin similar to that induced by a beta-arrestin-biased ligand to selectively stimulate receptor signaling in the absence of detectable G protein activation. Hearts from mice lacking beta-arrestin or AT1Rs failed to induce responses to mechanical stretch, as shown by blunted extracellular signal-regulated kinase and Akt activation, impaired transactivation of the epidermal growth factor receptor, and enhanced myocyte apoptosis. These data show that the heart responds to acute increases in mechanical stress by activating beta-arrestin-mediated cell survival signals.

Full Text

Duke Authors

Cited Authors

  • Rakesh, K; Yoo, B; Kim, I-M; Salazar, N; Kim, K-S; Rockman, HA

Published Date

  • June 8, 2010

Published In

Volume / Issue

  • 3 / 125

Start / End Page

  • ra46 -

PubMed ID

  • 20530803

Pubmed Central ID

  • 20530803

Electronic International Standard Serial Number (EISSN)

  • 1937-9145

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2000769

Language

  • eng

Conference Location

  • United States