Albuterol-induced downregulation of Gs alpha accounts for pulmonary beta(2)-adrenoceptor desensitization in vivo

The aim of the present study was to develop a chronic in vivo model of pulm onary beta(2)-adrenoceptor desensitization and to elucidate the nature and molecular basis of this state. Subcutaneous infusion of rats with albuterol for 7 days compromised the ability of albuterol, given acutely, to protect against acetylcholine-induced bronchoconstriction. The bronchoprotective e ffect of prostaglandin E-2, but not forskolin, was also impaired, indicatin g that the desensitization was heterologous and that the primary defect in signaling was upstream of adenylyl cyclase. beta(2)-Adrenoceptor density wa s reduced in lung membranes harvested from albuterol-treated animals, and t his was associated with impaired albuterol-induced cyclic adenosine monopho sphate (cAMP) accumulation and activation of cAMP-dependent protein kinase ex vivo. Gs alpha expression was reduced in the lung and tracheae of albute rol-treated rats, and cholera toxin-induced cAMP accumulation was blunted. Chronic treatment of rats with albuterol also increased cAMP phosphodiester ase activity and G protein-coupled receptor kinase-2, but the extent to whi ch these events contributed to beta(2)-adrenoceptor desensitization was unc lear given that forskolin was active in both groups of animals and that des ensitization was heterologous. Collectively, these results indicate that al buterol effects heterologous desensitization of pulmonary Gs-coupled recept ors in this model, with downregulation of Gs alpha representing a primary m olecular etiology.