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S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.

Publication ,  Journal Article
Hayashi, H; Hess, DT; Zhang, R; Sugi, K; Gao, H; Tan, BL; Bowles, DE; Milano, CA; Jain, MK; Koch, WJ; Stamler, JS
Published in: Mol Cell
May 3, 2018

Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis βarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within βarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting βarr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic βarrs with receptor-independent function. Enhanced βarr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking βarr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised β-adrenergic chronotropy and inotropy, reflecting βarr-biased transduction and β-adrenergic receptor downregulation. Thus, S-nitrosylation regulates βarr function and, thereby, biases transduction through GPCRs, demonstrating a novel role for nitric oxide in cellular signaling with potentially broad implications for patho/physiological GPCR function, including a previously unrecognized role in heart failure.

Duke Scholars

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Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

May 3, 2018

Volume

70

Issue

3

Start / End Page

473 / 487.e6

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • RAW 264.7 Cells
  • Nitric Oxide
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Ligands
 

Citation

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Hayashi, H., Hess, D. T., Zhang, R., Sugi, K., Gao, H., Tan, B. L., … Stamler, J. S. (2018). S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence. Mol Cell, 70(3), 473-487.e6. https://doi.org/10.1016/j.molcel.2018.03.034
Hayashi, Hiroki, Douglas T. Hess, Rongli Zhang, Keiki Sugi, Huiyun Gao, Bea L. Tan, Dawn E. Bowles, et al. “S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.Mol Cell 70, no. 3 (May 3, 2018): 473-487.e6. https://doi.org/10.1016/j.molcel.2018.03.034.
Hayashi H, Hess DT, Zhang R, Sugi K, Gao H, Tan BL, et al. S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence. Mol Cell. 2018 May 3;70(3):473-487.e6.
Hayashi, Hiroki, et al. “S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.Mol Cell, vol. 70, no. 3, May 2018, pp. 473-487.e6. Pubmed, doi:10.1016/j.molcel.2018.03.034.
Hayashi H, Hess DT, Zhang R, Sugi K, Gao H, Tan BL, Bowles DE, Milano CA, Jain MK, Koch WJ, Stamler JS. S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence. Mol Cell. 2018 May 3;70(3):473-487.e6.
Journal cover image

Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

May 3, 2018

Volume

70

Issue

3

Start / End Page

473 / 487.e6

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • RAW 264.7 Cells
  • Nitric Oxide
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Ligands