Inactivation of HERG potassium channels: Dynamic changes in the outer pore structure

HERG 钾通道失活：外孔结构的动态变化

• 批准号: nhmrc : 459402
• 负责人: A/Pr Serdar Kuyucak
• 金额: $ 28.19万
• 依托单位: Victor Chang Cardiac Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/inactivation-herg-potassium-pore-structure/97937
• 关键词: Inactivation; HERG; potassium; channels; Dynamic

Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic mechanisms underlying arrhythmias. The rhythm of the heart beat is controlled by electrical signals mediated by the flow of ions through specialised proteins called ion channels. Of the channels that contribute to cardiac electrical activity, potassium ion channels encoded by the Human ether-a-go-go-related gene (HERG) have been of particular interest for three reasons. Firstly, mutations in HERG are the cause of one third of cases of congenital long QT syndrome, an inherited cause of sudden cardiac death. Secondly, HERG is the molecular target for the vast majority of drugs that cause drug-induced long QT syndrome, the commonest cause of drug-induced arrhythmias and cardiac death. Thirdly, HERG channels have very unusual biophysical properties, which has led to the suggestion that they may act as an endogenous anti-arrhythmic agent . Accordingly, the major objective of the proposed research program is to understand the molecular and structural basis of the unusual properties of HERG channels. We will use a combination of molecular and electrical techiques in conjunction with computer modeling to probe the micoscopic motions in the channel that underly the unusual biophyscial properties of these channels. This work will facilitate a better understanding of how clinically identified mutations in HERG contribute to the increased risk of cardiac arrhythmias. More generally, it will improve our understanding of how cardiac ion channels maintain the normal rhythm of the heart.

由于心脏正常电活动的干扰而引起的心源性猝死是澳大利亚死亡的主要原因之一，其发病率正在增加。因此，解决心律失常的问题是心脏病学在21世纪世纪的主要挑战之一。有两个因素极大地限制了这一领域的进展，即无法预测谁的风险最大，以及缺乏治疗选择。为了解决这些问题，我们需要更好地了解心律失常的基本机制。心脏跳动的节奏是由电信号控制的，这些电信号是由通过称为离子通道的专门蛋白质的离子流介导的。在促进心脏电活动的通道中，由人类ether-a-go-go-related基因（HERG）编码的钾离子通道由于三个原因而特别感兴趣。首先，HERG突变是三分之一先天性长QT综合征病例的原因，这是心脏性猝死的遗传原因。其次，HERG是绝大多数药物的分子靶点，这些药物导致药物诱导的长QT综合征，这是药物诱导的心律失常和心源性死亡的最常见原因。第三，HERG通道具有非常不寻常的生物物理特性，这导致了它们可能充当内源性抗肿瘤剂的建议。因此，拟议的研究计划的主要目标是了解HERG通道的不寻常特性的分子和结构基础。我们将结合使用分子和电学技术与计算机建模来探测通道中的微观运动，这些运动是这些通道的不寻常生物特性的基础。这项工作将有助于更好地了解临床上确定的HERG突变如何导致心律失常风险增加。更一般地说，它将提高我们对心脏离子通道如何维持心脏正常节律的理解。