title: S-nitrosylation of beta-arrestin regulates beta-adrenergic receptor trafficking.
abstract: Signal transduction through G protein-coupled receptors (GPCRs) is regulated by receptor desensitization and internalization that follow agonist stimulation. Nitric oxide (NO) can influence these processes, but the cellular source of NO bioactivity and the effects of NO on GPCR-mediated signal transduction are incompletely understood. Here, we show in cells and mice that beta-arrestin 2, a central element in GPCR trafficking, interacts with and is S-nitrosylated at a single cysteine by endothelial NO synthase (eNOS), and that S-nitrosylation of beta-arrestin 2 is promoted by endogenous S-nitrosogluthathione. S-nitrosylation after agonist stimulation of the beta-adrenergic receptor, a prototypical GPCR, dissociates eNOS from beta-arrestin 2 and promotes binding of beta-arrestin 2 to clathrin heavy chain/beta-adaptin, thereby accelerating receptor internalization. The agonist- and NO-dependent shift in the affiliations of beta-arrestin 2 is followed by denitrosylation. Thus, beta-arrestin subserves the functional coupling of eNOS and GPCRs, and dynamic S-nitrosylation/denitrosylation of beta-arrestin 2 regulates stimulus-induced GPCR trafficking.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ozawa
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Whalen
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Nelson
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Mu
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Hess
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002417:Cattle; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D033962:Adaptor Protein Complex 2; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D002966:Clathrin; D008024:Ligands; D009603:Nitroso Compounds; D018343:Receptors, Adrenergic, beta-2; D026403:S-Nitrosothiols; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C021315:S-nitrosocysteine; D052250:Nitric Oxide Synthase Type III; D003545:Cysteine