Stimulation of many G protein-coupled receptors (GPCRs) increases cyclic adenosine monophosphate (cAMP) and nitric oxide (NO). While cAMP-dependent activation of protein kinase A (PKA) is a central regulatory mechanism, a parallel role for NO in GPCR transduction has not been established. Here we show that upon stimulation of multiple GPCRs in heart, brain, and fat, the regulatory subunits of PKA undergo enzymatic S-nitrosylation by SNO-CoA-assisted nitrosylase (SCAN). S-nitrosylation by SCAN is required for dissociation of PKA holoenzymes and activation of PKA. In transgenic and cardiovascular disease models, impaired adrenergic stimulation is identified with deficient S-nitrosylation of PKA, which can be rescued by the drug sodium nitroprusside. Our work suggests a new understanding of GPCR physiology with direct application to the clinical setting.
