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

Publication ,  Journal Article
Whalen, EJ; Foster, MW; Matsumoto, A; Ozawa, K; Violin, JD; Que, LG; Nelson, CD; Benhar, M; Keys, JR; Rockman, HA; Koch, WJ; Daaka, Y ...
Published in: Cell
May 4, 2007

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.

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Published In

Cell

DOI

ISSN

0092-8674

Publication Date

May 4, 2007

Volume

129

Issue

3

Start / End Page

511 / 522

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • S-Nitrosothiols
  • Receptors, Adrenergic, beta
  • Phosphorylation
  • Nitric Acid
  • Myocardium
  • Mice
  • Lung
 

Citation

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Whalen, E. J., Foster, M. W., Matsumoto, A., Ozawa, K., Violin, J. D., Que, L. G., … Stamler, J. S. (2007). Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell, 129(3), 511–522. https://doi.org/10.1016/j.cell.2007.02.046
Whalen, Erin J., Matthew W. Foster, Akio Matsumoto, Kentaro Ozawa, Jonathan D. Violin, Loretta G. Que, Chris D. Nelson, et al. “Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.Cell 129, no. 3 (May 4, 2007): 511–22. https://doi.org/10.1016/j.cell.2007.02.046.
Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, et al. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell. 2007 May 4;129(3):511–22.
Whalen, Erin J., et al. “Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.Cell, vol. 129, no. 3, May 2007, pp. 511–22. Pubmed, doi:10.1016/j.cell.2007.02.046.
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. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell. 2007 May 4;129(3):511–522.
Journal cover image

Published In

Cell

DOI

ISSN

0092-8674

Publication Date

May 4, 2007

Volume

129

Issue

3

Start / End Page

511 / 522

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • S-Nitrosothiols
  • Receptors, Adrenergic, beta
  • Phosphorylation
  • Nitric Acid
  • Myocardium
  • Mice
  • Lung