This Program Project focuses on the molecular basis for physiological control of myocardial electrical excitability and contractility by input from the autonomic nervous system and on the molecular basis for pharmacological modulation of these processes by major classes of cardioactive drugs. The major cardioactive hormones and neurotransmitters -- norepinephrine, epinephrine, and acetylcholine -- act via cell surface adrenergic receptors and muscarinic acetylcholine receptors to control cardiac function through a complex web of intracellular signaling processes. The cAMP and Ca signaling pathways are two major components of this regulatory web. Binding of agonists to cell surface receptors activates GTP-binding signal transduction proteins (G proteins) which in turn regulate the synthesis of second messengers and, in some cases, regulate major effector proteins such as ion channels. For example, G proteins activate adenylate cyclase resulting in increased synthesis of cAMP and increased phosphorylation of substrate proteins. The intracellular concentration of cAMP is also controlled in a critical way through its degradation by cyclic nucleotide phosphodiesterases. The activities of adenylate cyclase and phosphodiesterase are regulated by intracellular Ca, providing a key connection between the two major intracellular signaling pathways employing soluble second messengers. Each of these signaling mechanisms -- G proteins, cyclic nucleotides, Ca, and protein phosphorylation -- impinge on the ion channels which generate electrical signals in the heart. Much is known about cardiac physiology and regulatory control in the intact heart, and much is known about the signaling molecules that contribute to these regulatory processes. However, there is a wide gap in our knowledge of how the actions of critical classes of signaling proteins -- ion channels, receptors, kinases, and second messenger metabolizing enzymes -- are integrated at the cellular level and orchestrated in the intact heart to produce the intricate physiological regulation of cardiac function. In this Program Project, molecular and cellular approaches will be used to probe the mechanisms of action and pharmacological modulation of critical regulatory proteins, and targeted gene disruption in recombinant mice and physiological analysis of cardiovascular function in the resulting animals will provide insight into the roles of these key cellular regulators in cardiac function in vivo. Our research efforts will focus on five interrelated Projects and the research in these five Projects will be supported by four Cores. The Five Projects will focus on voltage-gated Na and Ca channels, cAMP-dependent protein kinases, muscarinic acetylcholine receptors, adenylyl cyclases, and cyclic nucleotide phosphodiesterases. They will be supported by an Administrative Core, a Protein Core, a Genetics Core, and a Cardiodynamics Core. This Program Project intends to add to our knowledge of the molecular properties and pharmacological modulation of these critical cardiac signaling proteins, and to till the gap between the knowledge at the molecular level and regulation in the cardiac cell and th e intact heart.
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