MOLECULAR CHARACTERIZATION OF CARDIAC NA+ CHANNELS

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Mammalian voltage-gated Na+ channels are encoded by a multigene family. The relationship of cardiac Na+ channel(s) to this family is currently unknown. "TTX- resistant" cardiac NA+ channels in other excitable tissue. Current evidence suggests that cardiac Na+ channel(s) most likely encoded by undiscovered genes within this multigene family. The broad long-term objectives of these studies are: 1) To determine to what extent the specialized functional properties of the cardiac Na+ channel(s) are accounted for by distinct gene sequences or by other modifications of known Na+ channel genes. 2) To characterize the distinct molecular structures of the cardiac Na+ channel(s) which account for these specialized functional properties. 3) To further elucidate properties of other members of the multigene family by comparison with the cardiac Na+ channel(s). 4) To determine mechanisms controlling cardiac Na+ channel expression, including these involved in differential expression of multiple Na+ channel isoforms in their respective tissues. The specific aims and experimental design to achieve these goals are: 1) To generate plasmid or bacteriophage cDNA libraries from P6 rat heart, and to screen these libraries with cRNA probes from the rat brain Na channel 11 sequence. 2) To analysis; 3) To determine the developmental, regional and tissue specific expression and functional properties of cardiac Na+ channel mRNAs. 4) To construct full-length cDNAs and to express them in heterologous systems including Xenopus oocytes and transfected mammalian cells, to determine which specialized functional properties of cardiac Na channels are encoded by the distinct sequence of the cardiac Na+ channel alpha-subunit. The health-related significance of this work is that the molecular basis of normal and abnormal cardiac impulse conduction will be elucidated, and a molecular basis for the design of more specific anti- arrhythmic agents determined.