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PMID: 18691971 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

S-nitrosylation of beta-arrestin regulates beta-adrenergic receptor trafficking.

Molecular cell ·Vol. 31 ·No. 3 ·2008-08-08 ·Pages 395-405

Ozawa K, Whalen EJ, Nelson CD, Mu Y, Hess DT, Lefkowitz RJ, Stamler JS

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.

MeSH Terms
Adaptor Protein Complex 2/metabolism Animals Arrestins/metabolism Cattle Cell Line Clathrin/metabolism Cysteine/analogs & derivatives,metabolism Endocytosis Humans Ligands Mice Models, Biological Nitric Oxide Synthase Type III/metabolism Nitroso Compounds/metabolism Protein Binding Protein Transport Receptors, Adrenergic, beta-2/metabolism S-Nitrosothiols/metabolism beta-Arrestin 2 beta-Arrestins
Chemicals
ARRB2 protein, human Adaptor Protein Complex 2 Arrb2 protein, mouse Arrestins Clathrin Ligands Nitroso Compounds Receptors, Adrenergic, beta-2 S-Nitrosothiols beta-Arrestin 2 beta-Arrestins S-nitrosocysteine Nitric Oxide Synthase Type III Cysteine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Ozawa Kentaro
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Whalen Erin J
Nelson Christopher D
Mu Yuanyu
Hess Douglas T
Lefkowitz Robert J
Stamler Jonathan S
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2008.05.024
Published
2008-08-08
Pages
395-405
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2630185
Subset
IM
Grants
NHLBI NIH HHS · P01 HL075443-040003 · United States
NHLBI NIH HHS · P01-HL075443 · United States
NHLBI NIH HHS · R01 HL070631-06 · United States
NIEHS NIH HHS · U19 ES012496 · United States
Howard Hughes Medical Institute · United States
NIEHS NIH HHS · U19 ES012496-05 · United States
NHLBI NIH HHS · R01 HL016037-35 · United States
NHLBI NIH HHS · R01 HL016037 · United States
NIEHS NIH HHS · U19-ES012496 · United States
NHLBI NIH HHS · P01 HL075443 · United States
NHLBI NIH HHS · R01-HL16037 · United States
NHLBI NIH HHS · R01 HL070631 · United States
NHLBI NIH HHS · R01-HL70631 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2008.05.024 PMC Full Text View journal details
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