S-nitrosylation of pVHL regulates β₂ adrenergic receptor function

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.