CARDIAC K+ CHANNEL GENE INTERACTIONS AND ARRHYTHMIAS

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Sudden cardiac death from arrhythmias accounts for more than 10 percent of naturally occurring deaths in the United States (1). Molecular genetics has recently identified ion channel mutations involved in hereditary Long-QT syndrome (LQTS) providing tools to further our insights into mechanisms of acquired arrhythmias (2). The major repolarizing K+ currents in human myocardiocytes are IKr and IKs. These currents are produced by HERG and KvLQT1, respectively. Mutations in these two genes and a cardiac Na+ channel gene, SCNA5, have been shown to cause some forms of hereditary LQTS (4,5,6,18). Heterologous expression of these cloned channels allows detailed study of their function, however, the phenotype of cloned channels frequently differs from their behavior in native tissue. These differences have been attributed to regulation by second messengers, accessory proteins, multiple splice variants or heterologous assembly of different subunits. Our lab has developed a mammalian expression system to study the functional and biochemical properties of cloned K+ channels, accessory proteins and their interactions. We have shown that HERG physically associates with another protein, minK, and that this association regulates IKr activity (7). Using this system, we also have evidence that a dominant negative HERG mutant acts by dramatically accelerating the degradation of wild-type HERG. We hypothesize that interaction of HERG with mutant HERG subunits, regulatory proteins such as minK, and second messengers modulates K+ current expression and propensity for ventricular arrhythmias. Accordingly, we propose to study the mechanisms of ventricular arrhythmias by investigating the regulation of HERG K+ channel expression and function. To this end we will: 1. Extend functional analysis of minK and HERG interaction. 2. Investigate the mechanism of alterated IKr expression by naturally occurring mutants of HERG. 3. Investigate second-messenger effects on HERG and HERG/minKK+ currents. 4. Perform a structural analysis of the interaction between HERG and minK.