Modulation of cardiac K+ channels by drugs

阻断快速延迟整流钾电流（Ikr）的药物会导致心脏动作电位延长和电不应性。 这些化合物是基于缺血诱导的室性心动过速和纤维性颤动的犬模型中的阳性发现而开发作为抗心律失常剂的。不幸的是，大多数III类抗心律失常药物，以及其他70种阻断Ikr作为副作用的常见介质，可引起心室动作电位的不均匀延长，并诱导长QT综合征及其相关的室性心律失常，尖端扭转型室性心动过速。 目前还不清楚为什么这么多结构不同的化合物阻断Ikr，但这种不良副作用现在被认为是开发新的安全药物的主要障碍。 最近的认识，阻断Ikr可以诱导心律失常，促使人们对开发IKs阻断剂作为抗心律失常药物的兴趣。 然而，在过去的5年中，发现编码共同组装形成Ikr（HERG和MiRP 1）或IK（KvLQT 1和minK）通道的α-和β-亚基的任何基因中的突变引起遗传性长QT综合征和猝死。该项目的总体目标源于我们在过去四年中的进展，其中我们定义了Ikr阻断的机制和有效III类抗肿瘤药物与HERG通道结合的分子决定因素。 我们现在建议表征阻断机制和结合位点的其他抗肿瘤药物和其他常用的药物，阻止Kr和Ks通道。 具体目的是表征HERG和KvLQT 1通道的高亲和力药物阻断的分子决定因素，失活状态在HERG通道的药物阻断中的作用，以及辅助β亚基（minK，MiRP 1和MiRP 2）的结合如何增强HERG和KvLQT 1通道的药物阻断。 了解药物与Kr和Ks通道结合的分子决定因素将有助于设计更安全的药物，这些药物没有诱导长QT综合征和潜在致命性心律失常的倾向。

Drugs that block the rapid delayed rectifier K+ current (Ikr) cause prolongation of cardiac action potentials and electrical refractoriness. These compounds were developed as antiarrhythmic agents based on positive findings in canine models of ischemia-induced ventricular tachycardia and fibrillation. Unfortunately, most class III antiarrhythmic drugs, as well as 70 other common mediations that block Ikr as a side-effect, can cause an inhomogeneous prolongation of ventricular action potentials and induce long QT syndrome and its associated ventricular arrhythmia, torsades de pointes. It is unclear why so many structurally diverse compounds block Ikr, but this undesirable side effect is now recognized as a major hurdle in the development of new and safe drugs. The recent awareness that block of Ikr can induce arrhythmias prompted interest in the development of IKs blockers as antiarrhythmic agents. However, in the past 5 years it was discovered that mutations in any of the genes that encode the alpha- and beta-subunits that co assemble to form Ikr (HERG and MiRPl or IKs (KvLQT1 and minK) channels cause inherited long QT syndrome and sudden death. The overall goal of this project arises from our progress during the past four years where we defined the mechanisms of Ikr block and the molecular determinants of binding of a potent class III antiarrhythmic agent to the HERG channel. We now propose to characterize the blocking mechanisms and binding site for additional antiarrhythmic agents and other commonly used medications that block Kr and Ks channels. The specific aims are to characterize the molecular determinants of high affinity drug block of HERG and KvLQT1 channels, the role of the inactivated state in drug block of HERG channels, and how binding of accessory beta-subunits (minK, MiRP1 and MiRP2) enhances drug block of HERG and KvLQT1 channels. An understanding of the molecular determinants of drug binding to Kr and Ks channels will facilitate design of safer drugs that are devoid of the propensity to induce the long QT syndrome and potentially fatal arrhythmias.