b2AR 脱敏和实验性哮喘需S-亚硝基化的参与
2022/08/19
摘要
背景：β2-肾上腺素能受体（β2AR）是一种原型 G 蛋白偶联受体（GPCR），是舒张支气管的强大驱动力，但 β-激动剂药物在哮喘中的有效性受到脱敏反应和快速抗药反应的限制。
方法与结果：本研究发现在激活过程中，β2AR 被 S-亚硝基化修饰，这对于 PKA 的经典脱敏以及介导支气管松弛的基于 NO 的信号的脱敏都是必不可少的。引人注目的是，在没有传统激动剂的情况下，单独的 S-亚硝基化可以驱动 β2AR 内化。对 S-亚硝基化（Cys265Ser）耐药的突变β2AR 表现出脱敏反应和内化作用降低，从而放大了基于 NO 的信号传导，具有 Cys265Ser 突变的小鼠对支气管收缩、炎症和哮喘的发展具有抵抗力。
结论：因此，S-亚硝基化是β2AR 信号传导的中心机制，可能在 GPCR 中广泛发挥作用，并以治疗增益为目标。
S-nitrosylation is required for β2AR desensitization and experimental asthma.
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
Abstract
BACKGROUND：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.
METHODS & RESULTS：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.
CONCLUSIONS：S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain
背景：β2-肾上腺素能受体（β2AR）是一种原型 G 蛋白偶联受体（GPCR），是舒张支气管的强大驱动力，但 β-激动剂药物在哮喘中的有效性受到脱敏反应和快速抗药反应的限制。
方法与结果：本研究发现在激活过程中，β2AR 被 S-亚硝基化修饰，这对于 PKA 的经典脱敏以及介导支气管松弛的基于 NO 的信号的脱敏都是必不可少的。引人注目的是，在没有传统激动剂的情况下，单独的 S-亚硝基化可以驱动 β2AR 内化。对 S-亚硝基化（Cys265Ser）耐药的突变β2AR 表现出脱敏反应和内化作用降低，从而放大了基于 NO 的信号传导，具有 Cys265Ser 突变的小鼠对支气管收缩、炎症和哮喘的发展具有抵抗力。
结论：因此，S-亚硝基化是β2AR 信号传导的中心机制，可能在 GPCR 中广泛发挥作用，并以治疗增益为目标。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Mol Cell. 2022 Aug 4:S1097-2765(22)00651-7. doi: 10.1016/j.molcel.2022.06.033)
(Mol Cell. 2022 Aug 4:S1097-2765(22)00651-7. doi: 10.1016/j.molcel.2022.06.033)
S-nitrosylation is required for β2AR desensitization and experimental asthma.
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
Abstract
BACKGROUND：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.
METHODS & RESULTS：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.
CONCLUSIONS：S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain
上一篇：
IL-37在慢性哮喘中通过IL-24信号通路逆转支气管上皮-间质转化防止气道重塑
下一篇：
过敏性致敏损害肺部常驻记忆CD8 T细胞反应和病毒清除
