The goal of the research proposed is to further understand the molecular basis of activation and inhibition of adenylate cyclase. A large number of hormones and drugs act by binding to cell surface receptors coupled to activation of adenylate cyclase and generation of cAMP intracellularly. Very often, the biological effects of these activating agents are countered or attenuated by agents which-recently-have been realized to inhibit adenylate cyclase and dampen the increases in intracellular cAMP induced by activating agents. for example, epinephrine and other beta-adrenergic catecholamines increase the strength and rate of beating of the heart by elevating intracellular cAMP levels. Acetylcholine, acting through muscarinic cholinergic receptors, attenuates the actions of epinephrine and decreases cardiac inotropy and chronotropy. The purpose of the present studies is to learn whether separate signaling systems or shared molecular components confer both activating and inhibiting information to adenylate cyclase using receptor binding and other established biochemical probes. It is hoped that such insights will provide arational basis for the design of drug and other therapeutic interventions in disease states characterized by altered hormonal responsiveness.
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