S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.

Published

Journal Article

Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis βarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within βarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting βarr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic βarrs with receptor-independent function. Enhanced βarr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking βarr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised β-adrenergic chronotropy and inotropy, reflecting βarr-biased transduction and β-adrenergic receptor downregulation. Thus, S-nitrosylation regulates βarr function and, thereby, biases transduction through GPCRs, demonstrating a novel role for nitric oxide in cellular signaling with potentially broad implications for patho/physiological GPCR function, including a previously unrecognized role in heart failure.

Full Text

Duke Authors

Cited Authors

  • Hayashi, H; Hess, DT; Zhang, R; Sugi, K; Gao, H; Tan, BL; Bowles, DE; Milano, CA; Jain, MK; Koch, WJ; Stamler, JS

Published Date

  • May 3, 2018

Published In

Volume / Issue

  • 70 / 3

Start / End Page

  • 473 - 487.e6

PubMed ID

  • 29727618

Pubmed Central ID

  • 29727618

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2018.03.034

Language

  • eng

Conference Location

  • United States