S-nitrosylation of pVHL regulates β2 adrenergic receptor function

• 成果类型: Article
• 署名作者: Grimmett, Zachary W.; Hayashi, Hiroki; Raffay, Thomas M.; Lin, Justin; Premont, Richard T.; Stamler, Jonathan S.
• 署名单位: University of Osaka; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; Case Western Reserve University Hospital; University Hospitals of Cleveland
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14971
• DOI: 10.1073/pnas.2515326122
• 发表日期: 2025-09-16
• 关键词: beta-adrenergic-receptors; protein-coupled receptor; targets; nitrosohemoglobin; denitrosylation; ubiquitination; identification; nitrosothiols; degradation; activation

摘要

The (32- adrenergic receptor ((32AR), a prototype G protein-coupled receptor, controls cardiopulmonary function underpinning O2 delivery. Abundance of the (32AR is canonically regulated by G protein-coupled receptor kinases and (3- arrestins, but neither controls constitutive receptor levels, which are dependent on ambient O2. Basal (32AR expression is instead regulated by the prolyl hydroxylase/pVHL- E3 ubiquitin ligase system, explaining O2 responsivity. Interplay between O2 and nitric oxide (NO, a potent bronchodilator) is central to cardiopulmonary function. Here, we demonstrate that pVHL- mediated (32AR degradation is counteracted by NO, revealing pVHL control of pulmonary function. NO S- nitrosylates Cys77 in human pVHL (cognate to mouse Cys43), which induces binding of the E3 ubiquitin ligase c- Cbl to degrade pVHL, thereby increasing (32AR expression. pVHL-C43S mutant mice refractory to S- nitrosylation exhibit decreases in (32AR signaling and increases in airway tone. Thus, pVHL controls adrenergic pulmonary function and contributes to bronchodilation by NO. Our findings suggest therapeutic approaches to asthma and obstructive airway disease.