This Program Project focuses on the molecular basis for physiological control of cardiovascular electrical excitability, contractility, and cell growth by input from the autonomic nervous system and on the molecular basis for pharmacological modulation of these processes by major classes of cardioactive drugs. Our proposed experimental approach combines methods from biochemistry, molecular and cellular biology, structural biology, electrophysiology, cardiovascular physiology, and mouse genetics in order to provide new insight into these regulatory processes at the molecular and structural levels and incorporate that insight into an integrated picture of the function of the cardiovascular system. In the proposed continuation of this Program Project, the molecular mechanisms for regulation of cardiac calcium (Ca) channels by several convergent signaling pathways will be elucidated. Molecular mechanisms of regulation of cellular signal transduction by cyclic nucleotide phosdiesterases will be determined. The structural basis for convergent regulation of Ca channels and cyclic nucleotide phosphodiesterases by intracellular signaling networks will be defined by NMR analysis. The sites and mechanisms of regulation of muscarinic acetylcholine receptors by intracellular signaling pathways will be determined and analyzed in vivo and mutant mice. In addition, the role of vascular smooth muscle myocytes will be studied using mice deficient in Type 3 adenylyl cyclase. Much is known about cardiac physiology and regulatory control in the intact heart, and much us 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, and second messenger metabolizing enzymes are integrated at the cellular level and orchestrated to produce the intricate physiological regulation of the cardiovascular system. This Program Project aims to add to our knowledge of the molecular and structural properties of critical cardiac signaling proteins, and to fill the gap between the knowledge at the molecular level and regulation in intact myocytes, heart, and cardiovascular system.
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