S-nitrosylation of pVHL regulates β(2) adrenergic receptor function.

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.