hERG Channel Assembly and Trafficking

描述(申请人提供)：Herg离子通道是获得性和遗传性长QT综合征(LQTS)的靶标，这种疾病会导致多形性室颤和猝死。本实验室以前的工作表明，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的潜在原因是LKR的丢失或减少。最近，我们发现了！KR通道的另一个亚单位，hERG1b。HERG1b由hERG1基因的另一个转录本编码，除了其氨基末端高度分化外，与hERG1a完全相同。这项建议探索了氨基末端的差异决定了异构体组装、内质网输出和质膜稳定性的机制。此外，我们建议对在一名未绘制图谱的LQTS患者中发现的突变进行表征，该突变可能代表第一个针对hERG1b的疾病突变。这些研究有望为钾通道组装的机制以及心律失常的分子机制提供新的见解。

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.