| First Author | Hayashi H | Year | 2018 |
| Journal | Mol Cell | Volume | 70 |
| Issue | 3 | Pages | 473-487.e6 |
| PubMed ID | 29727618 | Mgi Jnum | J:262395 |
| Mgi Id | MGI:6159328 | Doi | 10.1016/j.molcel.2018.03.034 |
| Citation | Hayashi H, et al. (2018) S-Nitrosylation of beta-Arrestins Biases Receptor Signaling and Confers Ligand Independence. Mol Cell 70(3):473-487.e6 |
| abstractText | Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and beta-arrestins (betaarr1 and betaarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-a-vis betaarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within betaarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting betaarr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic betaarrs with receptor-independent function. Enhanced betaarr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking betaarr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised beta-adrenergic chronotropy and inotropy, reflecting betaarr-biased transduction and beta-adrenergic receptor downregulation. Thus, S-nitrosylation regulates betaarr 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. |
