A reduction in airway beta-adrenoceptor density has been reported in cystic fibrosis lung but the mechanism underlying this defect remains unclear. In this study, we have investigated whether the decrease in beta2-adrenoceptor associates with altered G protein-coupled receptor kinase (GRK) levels. We assessed GRK activity by rhodopsin phosphorylation, and beta2-adrenoceptor and GRK at the mRNA and protein levels by Northern and Western blotting in peripheral lung samples from normal donors and patients with cystic fibrosis. GRK activity was significantly increased in peripheral cystic fibrosis lung with parallel increases in GRK2/5 mRNAs and protein expression. Functionally, isoproterenol-stimulated adenylyl cyclase activity was also diminished by 65% in cystic fibrosis lung homogenates. These data suggest that the increase in GRK activity may be one of the mechanisms underlying alterations in the coupling between beta2-adrenoceptor and adenylyl cyclase via G-protein and may thus contribute to the downregulation of beta2-adrenoceptor in cystic fibrosis lung.