The sympathetic nervous system has been implicated in the development of life threatening cardiac arrhythmias in a variety of pathophysiological settings, but particularly in the inherited forms of the long QT syndrome. The applicant indicates that a large gap currently exists in our understanding of the mechanisms responsible for the deleterious effects of adrenergic agonists and little is known about the action of the sympathetic system on mutant channels that underlie the long QT syndrome (LQTS). The goal of this proposal is to close this gap by combining electrophysiological and recombinant DNA techniques to characterize the effect of the adrenergic system on normal and mutant ion channels known to be responsible for LQTS (KvLQT1, HERG, SCN5A). The role of beta-1 and beta-2 adrenoceptor activation and phosphorylation by PKA and PKC will be evaluated for each channel in an attempt to establish a link between an abnormal respons of individual mutant channel to sympathetic activity. The study will provide further insights into the use and effectiveness of beta blockers and class 1B antiarrhythmic agents and define alternative pharmacological approaches for the different LQTS genotypes.
