S-nitrosylation of pVHL regulates β 2 adrenergic receptor function
Year: 2025
Type: article
Abstract: The β 2 -adrenergic receptor (β 2 AR), a prototype G protein–coupled receptor, controls cardiopulmonary function underpinning O 2 delivery. Abundance of the β 2 AR is canonically regulated by G protein–coupled receptor kinases and β-arrestins, but neither controls constitutive receptor levels, which are dependent on ambient O 2 . Basal β 2 AR expression is instead regulated by the prolyl hydroxylase/pVHL-E3 ubiquitin ligase system, explaining O 2 responsivity. Interplay between O 2 and nitric oxide (NO, a potent bronchodilator) is central to cardiopulmonary function. Here, we demonstrate that pVHL-mediated β 2 AR 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 β 2 AR expression. pVHL–C43S mutant mice refractory to S-nitrosylation exhibit decreases in β 2 AR 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.
Authors: Zachary W. Grimmett, Hiroki Hayashi, Thomas M. Raffay, Justin Lin, Richard T. Premont, Jonathan S. Stamler
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G2419897040, Medical Scientist Training Program, G3593636442, G4453228874, Gut Microbe-Derived Nitric Oxide As A Signal To Host: Role In Normal Physiology And In Disease, S-Nitrosoglutathione therapy for oxidant disease of the neonatal airways and lung, G6995303878, G7148773069, G7626856297, G7662419750, G8464692053, G864366698, G9000113854, Restoration and Function of S-Nitrosothiol in Stored Blood, Novel Regulation of Renal Function by S-Nitrosylation
OpenAlex ID: W4414081619