S-nitrosylation is required for β2AR desensitization and experimental asthma

Fabio V. Fonseca, Thomas M. Raffay, Kunhong Xiao, Precious J. McLaughlin, Zhaoxia Qian, Zachary W. Grimmett, Naoko Adachi, Benlian Wang, Alfred Hausladen, Brian A. Cobb, Rongli Zhang, Douglas T. Hess, Benjamin Gaston, Nevin A. Lambert, James D. Reynolds, Richard T. Premont, Jonathan S. Stamler

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The β2-adrenergic receptor (β2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the β2AR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive β2AR internalization in the absence of traditional agonist. Mutant β2AR refractory to S-nitrosylation (Cys265Ser) exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling, and mice with Cys265Ser mutation are resistant to bronchoconstriction, inflammation, and the development of asthma. S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain.

Original languageEnglish (US)
Pages (from-to)3089-3102.e7
JournalMolecular Cell
Volume82
Issue number16
DOIs
StatePublished - Aug 18 2022

Keywords

  • airway hyperreactivity
  • asthma
  • beta-agonist
  • caveolae
  • desensitization
  • nitric oxide
  • receptor internalization
  • S-nitrosylation
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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