Cardiac Ion Channel Regulation

心脏离子通道调节

• 批准号: 10085071
• 负责人: Isabelle Deschenes
• 金额: $ 51.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085071
• 关键词: Affect; Alternative Splicing; Arrhythmia; Automobile Driving; Binding; Brain; C-terminal; Calcium; Cardiac; Cardiac Myocytes; Cavia; Cell Nucleus; Cell membrane; Cell physiology; Cell surface; Cessation of life; Chronic stress; Cytoplasm; Cytoplasmic Organelle; Data; Developed Countries; Development; Dimensions; Disease; Disease Progression; Dissection; EF Hand Motifs; Event; Family; Funding; Genes; Genetic; Genetic Transcription; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Impairment; Importins; Investigation; Ion Channel; Kv channel-interacting protein 1; Kv4 channel; Lead; Location; MicroRNAs; Morbidity - disease rate; Muscle Cells; Myocardium; N-terminal; Names; Nuclear Pore Complex; Outcome; Palmitic Acylation Site; Pathogenesis; Pathway interactions; Potassium; Potassium Channel; Predisposition; Protein Isoforms; Proteins; RNA Splicing; Regulation; Regulatory Element; Role; RyR2; Source; Stress; Transcription Repressor; Variant; Ventricular; Work; acute stress; gene repression; heart function; indium arsenide; insight; mortality; novel; palmitoylation; presenilin; preservation; programs; protein distribution; protein expression; protein function; protein protein interaction; trafficking; voltage

Project Summary Cardiac arrhythmias are a leading cause of morbidity and mortality in developed nations, resulting in more than 300,000 deaths per year in the U.S. alone. These arrhythmias are frequently associated with acquired heart diseases, notably cardiac hypertrophy and heart failure (HF), where the dysregulation of a host of ion channels and transporters is observed. One of the most consistent changes frequently associated with compromised repolarization, is selective reduction in the transient outward potassium current Ito. Ito is generated primarily by the voltage-gated potassium (Kv) channel, Kv4, and its interacting auxiliary subunit known as K Channel Interacting Protein 2 (KChIP2). Under hypertrophy and HF there is consistent loss of KChIP2, thought to cause the reduction in Ito. Intriguingly, the loss in KChIP2 expression has been observed to be one of the earliest and most consistent remodeling events in HF development. The commonality and early state of this remodeling begins to suggest KChIP2 loss might not just be one of the casualties during disease progression, but may represent an initiating factor driving pathogenesis. Emerging evidence suggests KChIP2 may not be limited to cell surface regulation of Kv4. Indeed, since its original discovery, there has been an expansion in the roles of KChIP2 in cardiac ion channel function including modulation of Na, L-type Ca, and Kv1.5 channels. In total, there are four KChIP genes (KChIP1-4) with many alternatively spliced isoforms. Interestingly, KChIP3 (found in the brain), calsenilin and DREAM are encoded by a single gene. These names are the result of three independent discoveries due to different roles: modulation of Kv channels, regulation of the protein presenilin, and critically, calcium-sensitive transcriptional repression through binding to DRE (downstream regulatory element) sequences of genes. While KChIP2 is the only isoform found in the heart, given the homology it shares with KChIP3, it led us to hypothesize that KChIP2 could also perform multiple functions. Indeed, during the previous funding period, we identified a significantly expanded importance of KChIP2 in the heart. We demonstrated novel functions for KChIP2 in regulating calcium currents and RyR2. Importantly, we demonstrated a novel role for KChIP2 where it could regulate the genes at the source of INa and Ito by acting, much like KChIP3/DREAM, as a transcriptional repressor targeting a family of microRNAs. In this renewal, we will elucidate in aim 1 the role of KChIP2 as a transcriptional repressor. In aim 2, we will determine the control mechanisms for KChIP2 trafficking between cytoplasm and nucleus. And in aim 3, we will elucidate how chronic stress affects KChIP2 distribution and function in cardiac myocytes. Collectively, the outcomes of these investigations will demonstrate that KChIP2 actions are dramatically more expansive than modulation of Kv4 channels alone, suggesting that these other KChIP2 functions can be potent contributors to adverse remodeling events characterized in the diseased heart.

项目摘要 在发达国家，心律失常是发病率和死亡率的主要原因，导致超过 仅在美国每年就有30万人死亡。这些心律失常常常与获得性心脏有关。 疾病，特别是心肌肥厚和心力衰竭(HF)，其中宿主离子通道调节失调 并观察到了转运体。最一致的变化之一，经常与妥协相关 复极化，是选择性地降低瞬时外向钾电流Ito。ITO主要由以下方式生成 电压门控钾(Kv)通道Kv4及其相互作用的辅助亚基K通道 相互作用蛋白2(KChIP2)。在肥厚和心衰的情况下，KChIP2持续丢失，被认为是导致 伊藤忠的减少。有趣的是，KChIP2的表达缺失被观察到是最早和 心力衰竭发展中最一致的重塑事件。这种改造的共性和早期状态 开始提示KChIP2的丢失可能不仅是疾病进展过程中的伤亡之一，而且可能 代表了驱动发病机制的启动因素。新出现的证据表明，KChIP2可能不仅限于 Kv4的细胞表面调控。事实上，自从它最初被发现以来，它的作用已经扩大了 KChIP2在心脏离子通道中的作用包括对钠通道、L型钙通道和Kv1.5通道的调制。总体而言， 有四个KChIP基因(KChIP1-4)，有许多选择性剪接的异构体。有趣的是，KChIP3(位于 大脑)、钙化蛋白和梦都是由一个基因编码的。这些名字是由三个独立的 由于不同角色的发现：调节Kv通道，调节蛋白质早老素，以及关键的， 与DRE(下游调控元件)结合对钙敏感的转录抑制 基因序列。虽然KChIP2是在心脏中发现的唯一异构体，但考虑到它与 KChIP3，这使我们假设KChIP2也可以执行多种功能。事实上，在上一次 在资助期间，我们发现KChIP2在心脏中的重要性显著扩大。我们展示了一种新颖的 KChIP2在调节钙电流和RyR2中的作用重要的是，我们展示了一个新的角色 在KChIP2中，它可以通过与KChIP3/Dream一样的作用来调节Ina和Ito来源的基因，作为一个 以microRNA家族为靶标的转录抑制因子。在这次更新中，我们将在目标1中阐明 KChIP2作为转录抑制因子。在目标2中，我们将确定KChIP2贩运的控制机制 在细胞质和细胞核之间。在目标3中，我们将阐明慢性应激如何影响KChIP2分布 并在心肌细胞中发挥作用。总体而言，这些调查的结果将表明，KChIP2 动作比单独调制Kv4频道要广泛得多，这表明这些其他 KChIP2功能可能是疾病心脏中不良重塑事件的有力贡献者。