Kriti Rakesh1*, ByungSu Yoo1*†, Il-Man Kim1, Natasha Salazar1, Ki-Seok Kim1, and Howard A. Rockman1,2,3 ‡
1 Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Durham, NC 27710, USA.
2 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
* These authors contributed equally to this work.
† Present address: Department of Cardiology, Wonju College of Medicine, Yonsei University, 162 Ilsandong, Wonju 220-701, South Korea.
Abstract: β-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 β-arrestin-biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through β-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced β-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 β-arrestin similar to that induced by a β-arrestin-biased ligand to selectively stimulate receptor signaling in the absence of detectable G protein activation. Hearts from mice lacking β-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 β-arrestin-mediated cell survival signals.
‡ To whom correspondence should be addressed.
Citation: K. Rakesh, B. Yoo, I.-M. Kim, N. Salazar, K.-S. Kim, H. A. Rockman, β-Arrestin-Biased Agonism of the Angiotensin Receptor Induced by Mechanical Stress. Sci. Signal. 3, ra46 (2010).