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

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. [Display omitted] •S-nitrosylation of β-arrestins (βarrs) by n/iNOS suppresses canonical βarr function•S-nitrosylation provides a general mechanism to bias GPCR signaling via G proteins•S-nitrosylation of βarrs also enables ligand-independent βarr function•S-nitrosylation of βarr2 critically supports adrenergic function in failing hearts S-nitrosylation, the ubiquitous nitric oxide-derived post-translational modification of proteins, inhibits the canonical function of β-arrestins to promote preferential G protein signaling (“bias”) via G protein-coupled receptors. This general mechanism for biased signaling profoundly affects the severity of heart failure and provides a novel function for nitric oxide broadly.