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

心脏猝死是由于心脏的正常电活动受到干扰而导致的，是澳大利亚的主要死亡原因之一，而且发病率正在上升。因此，解决心律失常问题是21世纪心脏病学面临的主要挑战之一。两个因素在很大程度上限制了这一领域的进展，即无法预测谁面临最大的风险，以及治疗选择的匮乏。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。心跳的节律是由电信号控制的，电信号是由离子流经称为离子通道的特殊蛋白质所介导的。在参与心脏电活动的通道中，由人类乙醚相关基因(HERG)编码的钾离子通道引起了人们的特别兴趣，原因有三。首先，HERG基因突变是三分之一先天性长QT综合征的原因，这是一种导致心脏性猝死的遗传性原因。其次，HERG是导致药物诱导的长QT综合征的绝大多数药物的分子靶点，药物诱导的长QT综合征是药物引起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，这使得人们认为它们可能是一种内源性抗心律失常药物。因此，建议的研究计划的主要目标是了解HERG通道异常特性的分子和结构基础。我们将结合分子和电子技术结合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不同寻常的生物物理特性的基础。这项工作将有助于更好地理解临床发现的HERG突变是如何导致心律失常风险增加的。更广泛地说，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。

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.