MECHANISMS OF THE VOLTAGE-DEPENDENT SODIUM CHANNEL

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An interdisciplinary approach will be used to elucidate the structure and function of the voltage-dependent sodium channel from E. electrophorus electroplax. Biochemical methods will be employed to study the binding of tetrodotoxin and saxitoxin to a component of the sodium channel, and factors affecting the equilibrium and kinetic binding parameters of toxin-binding in intact membranes and detergent extracts will be determined and compared. This will hopefully increase our understanding of the molecular nature of the toxin binding site, and help determine its relationship to the channel component responsible for ion selectivity. Immunological methods will be used to ascertain whether the purified tetrodotoxin/saxitoxin binding site is associated with molecular structures responsible for other channel functionalities, such as voltage-sensitive gating. Antibodies will be raised to purified toxin sites, with the goal of generating physiologically-active antibodies affecting other sodium channel sites. Such antibodies could be used chemical probes and labels with which to correlate various sodium channel functions with their corresponding structures, and as a means to determine sodium channel in certain autoimmune neuromuscular diseases. Electrophysiological methods, mainly voltage-clamp studies, will be used to determine the functional affects of immunological and biochemical compounds.