APPROACHING ARRHYTHMIA THERAPY THROUGH NA CHANNEL GATING

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Ventricular tachyarrhythmias are a major health concern because they are a chief cause of sudden death in coronary artery disease - of which they may be the first manifestation - and chronic congestive heart failure syndromes. The usual therapy is blockade of ion channels, particularly Na channels, but the drugs are often ineffective and sometimes have severe central nervous system side effects. The long term goal of the research in this proposal is to develop a new framework for the design of anti- arrhythmic drugs. The short term goals are to (1) identify the parts of the Na channel molecule that are responsible for its inactivation, or closing during a sustained stimulus, and (2) to identify differences in the mechanism between cardiac and brain Na channels. This should allow design of effective antiarrhythmic drugs which do not have central nervous system side effects. The goals will be accomplished using the two powerful techniques of recombinant DNA technology and single ion channel current analysis to study, initially, the type III Na channel from rat brain expressed in Xenopus oocytes. Cardiac and brain Na channels have functionally different mechanisms of inactivation, as cardiac Na channels tend to reopen during a depolarizing stimulus and brain Na channels do not. Pilot experiments have shown that the type III Na channel molecule has both types of inactivation patterns, and that selective mutations in the intracellular region linking domains III and IV have large effects on Na channel inactivation. Specifically, conservative substitutions for strategically placed, positively charged lysines remarkably speed up the rate of inactivation and alter single channel kinetic parameters. Through study of the effects of more mutations in this area of the molecule, a molecular mechanism for brain Na channel inactivation should be defined. This may be compared and contrasted with the behavior of cloned cardiac Na channels, once they are available.