The applicant hypothesizes that physiological and pharmacological stimuli induce changes in voltage-gated potassium and calcium channel gene expression that in turn alter myocyte excitability in the heart. Biochemical, immunohistochemical, and electrophysiological experiments are proposed to test hypotheses that; 1) dexamethasone regulates cardiomyocyte voltage-gated K+ and Ca2+ currents in action potentials; 2) dexamethasone induces increases in channel mRNAs and cell-surface channel proteins in cardiomyocytes and in the case of Kv1.5 this will be evident as an increase at the intercalated disc; 3) dexamethasone acts directly on cultured adult cardiomyocytes to alter channel gene expression; and 4) altering the synthesis of a single Kv1 subunit can affect the expression of multiple homomeric and/or heteromeric potassium channels. These studies will determine if hormonal control of K+ and Ca2+ channel expression is a novel mechanism for long-term regulation of cardiac excitability.
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