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

ABSTRACT: Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and ?-arrestins (?arr1 and ?arr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis ?arr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within ?arr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting ?arr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic ?arrs with receptor-independent function. Enhanced ?arr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking ?arr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised ?-adrenergic chronotropy and inotropy, reflecting ?arr-biased transduction and ?-adrenergic receptor downregulation. Thus, S-nitrosylation regulates ?arr 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.

SUBMITTER: Hayashi H 

PROVIDER: S-EPMC5940012 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature