hERG Channel Assembly and Trafficking

hERG 渠道组装和贩运

• 批准号: 7119989
• 负责人: Gail A Robertson
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119989
• 关键词: SDS polyacrylamide gel electrophoresis; Xenopus oocyte; density gradient ultracentrifugation; electrophysiology; gene mutation; immunoprecipitation; intracellular transport; ion transport; long QT syndrome; membrane channels; molecular assembly /self assembly; nuclear magnetic resonance spectroscopy; potassium channel; protein transport; sudden cardiac death; voltage gated channel; western blottings

DESCRIPTION (provided by applicant): hERG ion channels are the target for acquired and inherited long QT syndrome (LQTS), diseases leading to polymorphic ventricular fibrillation and sudden death. Previous work in this lab demonstrated that hERGIa subunits are a major component of channels producing the ventricular repolarizing current lKr, thus explaining the underlying cause of LQTS-2 as a loss or reduction of lKr. Most recently, we have identified another subunit of !Kr channels, hERG1b. Encoded by an alternate transcript of the hERG1 gene, hERG1b is identical to hERG1a except for its amino terminus, which is highly divergent. This proposal explores mechanisms by which the differences in the amino termini specify heteromeric assembly, export from the endoplasmic reticulum and stability within the plasma membrane. In addition, we propose to characterize a mutation found in an unmapped LQTS patient potentially representing the first disease mutation specific to hERG1b. These studies are expected to provide novel insights into mechanisms of potassium channel assembly as well as the molecular mechanisms of cardiac arrhythmias.

描述（由申请人提供）：hERG 离子通道是获得性和遗传性长 QT 综合征（LQTS）、导致多形性心室颤动和猝死的疾病的靶标。该实验室之前的工作表明，hERGIa 亚基是产生心室复极电流 lKr 的通道的主要组成部分，从而解释了 LQTS-2 的根本原因是 lKr 的损失或减少。最近，我们发现了！Kr 通道的另一个亚基，hERG1b。 hERG1b 由 hERG1 基因的替代转录物编码，除了氨基末端高度不同外，与 hERG1a 相同。该提案探讨了氨基末端差异指定异聚体组装、内质网输出和质膜内稳定性的机制。此外，我们建议表征在未定位的 LQTS 患者中发现的突变，该突变可能代表第一个特定于 hERG1b 的疾病突变。这些研究有望为钾通道组装机制以及心律失常的分子机制提供新的见解。