Inflammatory and contractile agents sensitize specific adenylyl cyclase isoforms in human airway smooth muscle

beta-agonists, through activation of the beta(2)-adrenergic receptor (beta( 2)AR)-G(s)-adenylyl cyclase (AC) pathway, promote bronchodilation via funct ional antagonism of airway smooth muscle (ASM) spasmogens associated with t he asthmatic state. Although previous studies have demonstrated that beta(2 )AR signaling in ASM is subject to homologous (beta-agonist-induced) beta(2 )AR desensitization, the potential for inflammatory and contractile agents to impact beta(2)AR signaling in ASM through heterologous mechanisms has no t been defined. Here we report that chronic exposure of human ASM (HASM) to carbachol, serotonin, the thromboxane analogue U46619, or histamine induce d little change or a small increase in isoproterenol-stimulated cyclic aden osine monophosphate (cAMP) formation, but significantly increased cAMP form ation elicited by stimulation with forskolin. This latter increase in intri nsic AC activity was largely reversed by pertussis toxin pretreatment, and was unaffected by protein kinase C inhibition. Analysis of both AC function and isoform expression supports a dominant role of AC VI in HASM, and poin ts to important differences in ASM AC isoform expression among species. Add itional studies identify AC as the limiting component in beta(2)AR-G(s)-AC signaling in HASM, and thus a potentially important target of therapeutic s trategies designed to influence airway contractile state.