Regulation of Cardiac Ion Channel Expression

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DESCRIPTION (the applicant's description verbatim): The function of electrically excitable cells depends on expressing appropriate levels of a variety of voltage-gated ion channels. This is particularly important in the heart because aberrant ion channel activity can promote the incidence of arrhythmias and sudden death. In the current funding period, we showed that hormones and renovascular hypertension, which is associated with hypertrophy, regulate cardiac voltage-gated potassium (Kv) channel gene expression. Furthermore, we discovered two post-translational effects that control expression of Kv channels. Here we will continue to study these mechanisms that affect expression of cardiac Kv channels. First, we have discovered that native Kvb2 subunits that were previously shown to interact with the N-terminus of Kv1 family channels are associated with Kv4.3 channels. This association requires the C-terminal region of Kv4.3 and enhances protein expression and activity of these transient outward current channels. Aim 1 will determine the molecular basis of the novel interaction, and elucidate how the auxiliary subunit increases channel expression. Second, we have identified a three amino acid motif near the C-terminus of Kv1 channels that governs cell surface expression. Deletion of the motif, which occurs in some genetic diseases, inhibits complete glycosylation and localization of channels in the plasma membrane. Furthermore, natural variations in the motif account for many differences among wild type Kv1 family members. Aim 2 will explore how the VXXSL motif governs processing and surface expression of Kv1 channels. Third, we have found that the hypertrophy inducers phenylephrine and Angiotensin II downregulate Kv4.3 mRNA and protein in cultured cardiomyocytes. Although both of these agents activate Gq-coupled receptors, it appears that they use distinct mechanisms to change the expression of the channel. Aim 3 will determine the molecular and signaling mechanisms used by phenylephrine and Angiotensin II to reduce K4.3 gene transcription and mRNA stability. These studies will identify and elucidate novel mechanisms that control Kv channel expression. The understanding of such mechanisms may aid in the development of drugs to regulate channel expression with the goal of reducing the incidence of arrhythmias and sudden death.