Funds are requested to continue support of studies of the pharmacology and regulation of ion channels and carrier transport proteins in the membrane of enzymatically dispersed single cardiac myocytes from guinea- pig. We will use both whole-cell and single channel recording techniques to study three major areas: (i) L-type calcium channels and their modulation by pharmacological agonists and antagonists, (ii) the properties and regulation of delayed rectifier potassium channels, and (iii) the properties and regulation of electrogenic Na-Ca exchange. During previous years of support, important new information on the mechanism of action and specificity of calcium channel agonists and antagonists was obtained. In the proposed studies we will further assess the interaction of these compounds with the inactivation process of L-type calcium channels and gain a better understanding of the role of phosphorylation and GTP binding proteins in channel inactivation. Delayed rectifier potassium channels will be studied in an attempt to better understand the gating properties of underlying channels and the intracellular regulatory pathways involved in the control of these channels by the autonomic nervous system. Finally, in recent studies, we have identified ionic currents which are generated by a Na-Ca exchange mechanism in isolated myocytes and we propose new studies to examine the relationship between these currents, changes in intracellular calcium and cell shortening. The results of these studies should provide new fundamental information about the properties of channels and exchange carriers in heart and a better understanding of excitation-contraction coupling and its modulation by pharmacological agents.
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