Proc Natl Acad Sci U S A. 2025 Sep 16;122(37):e2515326122. doi: 10.1073/pnas.2515326122. Epub 2025 Sep 9.
ABSTRACT
The β2-adrenergic receptor (β2AR), a prototype G protein-coupled receptor, controls cardiopulmonary function underpinning O2 delivery. Abundance of the β2AR is canonically regulated by G protein-coupled receptor kinases and β-arrestins, but neither controls constitutive receptor levels, which are dependent on ambient O2. Basal β2AR 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 β2AR 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 β2AR expression. pVHL-C43S mutant mice refractory to S-nitrosylation exhibit decreases in β2AR 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.
PMID:40924457 | DOI:10.1073/pnas.2515326122
