| First Author | Fonseca FV | Year | 2022 |
| Journal | Mol Cell | Volume | 82 |
| Issue | 16 | Pages | 3089-3102.e7 |
| PubMed ID | 35931084 | Mgi Jnum | J:342739 |
| Mgi Id | MGI:7335901 | Doi | 10.1016/j.molcel.2022.06.033 |
| Citation | Fonseca FV, et al. (2022) S-nitrosylation is required for beta2AR desensitization and experimental asthma. Mol Cell 82(16):3089-3102.e7 |
| abstractText | The beta2-adrenergic receptor (beta2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of beta-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the beta2AR 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 beta2AR internalization in the absence of traditional agonist. Mutant beta2AR 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 beta2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain. |
