Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.

Published

Journal Article

beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent the loss of beta-AR signaling in vivo, but the molecular details are unknown. Here we show in mice that SNOs increase beta-AR expression and prevent agonist-stimulated receptor downregulation; and in cells, SNOs decrease GRK2-mediated beta-AR phosphorylation and subsequent recruitment of beta-arrestin to the receptor, resulting in the attenuation of receptor desensitization and internalization. In both cells and tissues, GRK2 is S-nitrosylated by SNOs as well as by NO synthases, and GRK2 S-nitrosylation increases following stimulation of multiple GPCRs with agonists. Cys340 of GRK2 is identified as a principal locus of inhibition by S-nitrosylation. Our studies thus reveal a central molecular mechanism through which GPCR signaling is regulated.

Full Text

Duke Authors

Cited Authors

  • Whalen, EJ; Foster, MW; Matsumoto, A; Ozawa, K; Violin, JD; Que, LG; Nelson, CD; Benhar, M; Keys, JR; Rockman, HA; Koch, WJ; Daaka, Y; Lefkowitz, RJ; Stamler, JS

Published Date

  • May 4, 2007

Published In

Volume / Issue

  • 129 / 3

Start / End Page

  • 511 - 522

PubMed ID

  • 17482545

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2007.02.046

Language

  • eng

Conference Location

  • United States