@article{178d7ada892a477780a831deea14a7d6,
title = "S-nitrosylation is required for β2AR desensitization and experimental asthma",
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.",
keywords = "airway hyperreactivity, asthma, beta-agonist, caveolae, desensitization, nitric oxide, receptor internalization, S-nitrosylation, β-adrenergic receptor",
author = "Fonseca, {Fabio V.} and Raffay, {Thomas M.} and Kunhong Xiao and McLaughlin, {Precious J.} and Zhaoxia Qian and Grimmett, {Zachary W.} and Naoko Adachi and Benlian Wang and Alfred Hausladen and Cobb, {Brian A.} and Rongli Zhang and Hess, {Douglas T.} and Benjamin Gaston and Lambert, {Nevin A.} and Reynolds, {James D.} and Premont, {Richard T.} and Stamler, {Jonathan S.}",
note = "Funding Information: The authors thank Puneet Seth for technical assistance, and Robert Lefkowitz, Howard Rockman (Duke University), and Walter Koch (Temple University) for helpful discussions. Funded by NIH grants P01 HL075443 , P01 HL128192 , P01 HL158507 , R01 HL126900 , and R01 DK119506 . Funding Information: The authors thank Puneet Seth for technical assistance, and Robert Lefkowitz, Howard Rockman (Duke University), and Walter Koch (Temple University) for helpful discussions. Funded by NIH grants P01 HL075443, P01 HL128192, P01 HL158507, R01 HL126900, and R01 DK119506. Conceptualization, F.V.F. and J.S.S.; methodology, F.V.F. T.M.R. B.W. A.H. J.D.R. and N.A.L.; formal analysis, F.V.F. T.M.R. D.T.H. N.A.L. R.T.P. and J.S.S.; investigation, F.V.F. T.M.R. K.X. B.W. P.J.M. Z.Q. Z.W.G. A.H. N.A. D.T.H. B.A.C. N.A.L. and R.T.P.; writing—original draft, R.T.P. and F.V.F.; writing—review and editing, T.M.R. B.A.C. and J.D.R.; and supervision, project administration, and funding acquisition, J.S.S. J.S.S. has patents relating to nitrosylation, is a founder of SNO bio, and serves as a paid consultant to NNOXX, which is developing NO-based technology. CWRU and UHCMC have management plans in place. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = aug,
day = "18",
doi = "10.1016/j.molcel.2022.06.033",
language = "English (US)",
volume = "82",
pages = "3089--3102.e7",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "16",
}