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Am. J. Respir. Cell Mol. Biol., Volume 21, Number 5, November, 1999 597-606

Inflammatory and Contractile Agents Sensitize Specific Adenylyl Cyclase Isoforms in Human Airway Smooth Muscle

Charlotte K. Billington, Ian P. Hall, Stuart J. Mundell, Jean-Luc Parent, Reynold A. Panettieri Jr., Jeffrey L. Benovic, and Raymond B. Penn

Department of Therapeutics, Institute of Cell Signalling, University Hospital of Nottingham, Nottingham, United Kingdom; Division of Pulmonary and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine; and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania

beta -agonists, through activation of the beta 2-adrenergic receptor (beta 2AR)-Gs-adenylyl cyclase (AC) pathway, promote bronchodilation via functional antagonism of airway smooth muscle (ASM) spasmogens associated with the asthmatic state. Although previous studies have demonstrated that beta 2AR signaling in ASM is subject to homologous (beta -agonist-induced) beta 2AR desensitization, the potential for inflammatory and contractile agents to impact beta 2AR signaling in ASM through heterologous mechanisms has not been defined. Here we report that chronic exposure of human ASM (HASM) to carbachol, serotonin, the thromboxane analogue U46619, or histamine induced little change or a small increase in isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) formation, but significantly increased cAMP formation elicited by stimulation with forskolin. This latter increase in intrinsic 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 points to important differences in ASM AC isoform expression among species. Additional studies identify AC as the limiting component in beta 2AR-Gs-AC signaling in HASM, and thus a potentially important target of therapeutic strategies designed to influence airway contractile state.




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