hERG Channel Assembly and Trafficking

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）的靶点，LQTS是导致多形性室颤和猝死的疾病。本实验室先前的工作表明，hERGIa亚单位是产生心室复极化电流IKr的通道的主要成分，因此将LQTS-2的根本原因解释为IKr的损失或减少。最近，我们发现了另一个亚基！Kr通道，hERG 1b。hERG 1b由hERG 1基因的替代转录物编码，除了其氨基末端高度不同外，hERG 1b与hERG 1a相同。该建议探讨了氨基末端的差异指定异聚体组装、从内质网出口和质膜内稳定性的机制。此外，我们建议对未定位的LQTS患者中发现的突变进行表征，该突变可能代表hERG 1b特异性的第一种疾病突变。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。

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.