MODULATION OF CARDIAC REPOLARIZATION

Vanderbilt University, Nashville TN

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Abstract

Heterogeneity of action potential duration is an important feature of normal and abnormal cardiac electrophysiology. During the previous period of support, studies in our laboratory and elsewhere have identified the concept, to be further tested here, that expression of multiple genes is required for the faithful recapitulation of ion currents involved in cardiac repolarization. The proposed research will focus on two currents whose dysfunction can modulate action potential duration: INa and IKr. There are 3 Specific Aims. (1) Our previous in vitro studies have suggested that INa undergoes a maturation process in vitro determined by an interaction between alpha and beta1 channel subunits. This maturation also appears to be determined by activation of intracellular signaling systems such as cAMP-dependent processes. An immature INa inactivates slowly, and so may contribute to plateau ion current. The goal of Specific Aim #1 is to further test the hypothesis that a mature cardiac INa is determined by an alpha-beta1 interaction. The studies will be conducted both in vitro (in cultured cells) and in vivo (during development and with administration of a toxin, evaluated during the previous period of support, that destroys sympathetic neurons). (2) We have identified a C-terminal splice variant of HERG, the gene that encodes IKr mRNA encoding the splice variant is twice as abundant as that of canonical HERG in normal heart while in patients with advanced congestive heart failure, we have found a striking decrease in expression of the splice variant only. Studies in Specific Aim #2 will determine the functional role of the HERG splice variant in IKr physiology. (3) We have found that suppression of expression of minK reduced IKr amplitude. This finding, as well as the recent identification of minK partnering with KvLQT1 (another six-membrane spanning segment K+ channel), suggests the hypothesis to be tested in Specific Aim #3, that expression of minK modifies function of other six- membrane spanning segment K+ channels. This research program will further increase our understanding of the mechanisms whereby subunit expression determines the functional characteristics of cardiac ion currents that play an important role during cardiac repolarization. New knowledge in the broad area of the molecular basis of arrhythmogenesis is a crucial step to development of improved therapies for cardiac arrhythmias.