S-nitrosylation is essential for β2AR desensitization and experimental asthma

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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, and receptor S-nitrosylation is essential for both classic desensitization by PKA as well as desensitization of newly-appreciated NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive β2AR internalization in the absence of traditional agonist. Mutant β2AR(Cys265Ser) refractory to S-nitrosylation exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling. Mice with β2AR-Cys265Ser 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.