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

doi:10.1016/j.molcel.2022.06.033

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

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

5 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 language	English (US)
Pages (from-to)	3089-3102.e7
Journal	Molecular Cell
Volume	82
Issue number	16
DOIs	https://doi.org/10.1016/j.molcel.2022.06.033
State	Published - Aug 18 2022

Keywords

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

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2022.06.033

Cite this

Fonseca, F. V., Raffay, T. M., Xiao, K., McLaughlin, P. J., Qian, Z., Grimmett, Z. W., Adachi, N., Wang, B., Hausladen, A., Cobb, B. A., Zhang, R., Hess, D. T., Gaston, B., Lambert, N. A., Reynolds, J. D., Premont, R. T., & Stamler, J. S. (2022). S-nitrosylation is required for β₂AR desensitization and experimental asthma. Molecular Cell, 82(16), 3089-3102.e7. https://doi.org/10.1016/j.molcel.2022.06.033

Fonseca, FV, Raffay, TM, Xiao, K, McLaughlin, PJ, Qian, Z, Grimmett, ZW, Adachi, N, Wang, B, Hausladen, A, Cobb, BA, Zhang, R, Hess, DT, Gaston, B, Lambert, NA, Reynolds, JD, Premont, RT & Stamler, JS 2022, 'S-nitrosylation is required for β₂AR desensitization and experimental asthma', Molecular Cell, vol. 82, no. 16, pp. 3089-3102.e7. https://doi.org/10.1016/j.molcel.2022.06.033

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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.",

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AU - Fonseca, Fabio V.

AU - Raffay, Thomas M.

AU - Xiao, Kunhong

AU - McLaughlin, Precious J.

AU - Qian, Zhaoxia

AU - Grimmett, Zachary W.

AU - Adachi, Naoko

AU - Wang, Benlian

AU - Hausladen, Alfred

AU - Cobb, Brian A.

AU - Zhang, Rongli

AU - Hess, Douglas T.

AU - Gaston, Benjamin

AU - Lambert, Nevin A.

AU - Reynolds, James D.

AU - Premont, Richard T.

AU - Stamler, Jonathan S.

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N2 - 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.

AB - 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.

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KW - β-adrenergic receptor

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