Regulation of Cardiac Ion Channel Expression

描述（申请人的逐字描述）： 电兴奋细胞依赖于表达适当水平的 多种电压门控离子通道。这一点尤其重要， 心脏因为异常的离子通道活动可以促进发病率 心律失常和猝死。在当前的融资期内，我们表明， 激素和肾血管性高血压，这与肥大有关， 调节心脏电压门控钾（Kv）通道基因表达。 此外，我们还发现了两种翻译后效应， Kv通道的表达。我们将继续研究这些机制， 影响心脏Kv通道的表达。 首先，我们发现，先前显示的天然Kvb 2亚基 与Kv 1家族通道的N末端相互作用， Kv4.3频道。这种关联需要Kv4.3的C-末端区域， 增强这些瞬时外向电流的蛋白质表达和活性 渠道目标1将确定新相互作用的分子基础， 并阐明辅助亚基如何增加通道表达。 第二，我们已经确定了一个三个氨基酸的基序附近的C-末端的Kv 1 控制细胞表面表达的通道。删除主题， 发生在某些遗传性疾病中，抑制完全糖基化， 质膜中通道的定位。此外，自然 基序的变异解释了野生型Kv 1家族之间的许多差异 成员目标2将探讨VXXSL基序如何控制加工和表面 Kv 1通道的表达。 第三，我们已经发现肥大诱导物苯肾上腺素和 血管紧张素II下调心肌细胞Kv4.3 mRNA和蛋白表达。 虽然这两种药物都能激活Gq偶联受体，但似乎 它们使用不同的机制来改变通道的表达。目标3 将决定苯乙醯胺使用的分子和信号机制， 血管紧张素II降低K4.3基因转录和mRNA稳定性。 这些研究将确定和阐明控制Kv的新机制 渠道表达。了解这些机制可能有助于 开发调节通道表达的药物， 心律失常和猝死的发生率。

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.