K+ Channel Inactivation and Antiarrhythmic Drug Action

K 通道失活和抗心律失常药物作用

• 批准号: 6769930
• 负责人: Randall L. RASMUSSON
• 金额: $ 31.4万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769930
• 关键词: Xenopus oocyte; antiarrhythmic agent; cardiovascular pharmacology; conformation; ion channel blocker; pharmacokinetics; potassium channel; site directed mutagenesis; voltage /patch clamp

DESCRIPTION (provided by applicant): There has been increased interest in the clinical application of Class Ill (K+ channel blockers) as anti-arrhythmic agents. Unfortunately, reduction of the HERG current or other slow delayed rectifiers has been demonstrated to be proarrhythmic, both in abnormalities in coding genes or following pharmacologic intervention. This has placed renewed interest in the rapidly activating K+ currents that are important during the earlier phases of the cardiac action potential in various regions of the heart. However, K+ channel blockers vary in their selectivity for each K+ channel type, and display a variety of conformation specific interactions with K+ channels. Such conformation specific interactions can cause the degree of block of a channel to vary by orders of magnitude depending on the pattern of electrical stimulation. Such conformation dependent binding can be either detrimental or beneficial. This proposal focuses on examining the relationship between antiarrhythmic drug binding and a particular class of conformation changes, namely C-type inactivation in cardiac K+ channels. C-type inactivation is more widely distributed among cardiac K+channels than N-type and may be the dominant determinant of such important properties as recovery, K+sensitivity, pHo sensitivity and drug use-dependence. The goal of this proposal is to elucidate how C-type inactivation can influence the complex patterns of block and use-dependence seen with Class III agents in the cardiac channels, Kv1.4, Kvl.5 and Kv4.3. The main hypothesis of this proposal is that C-type inactivation involves a rearrangement of the intracellular pore resulting in its closure or partial closure. We further hypothesize that rotation of S6 is a critical event in this process and accounts for coupling of intracellular closure to the extracellular conformation changes in the S5-H5 linker region and the H5-S6linker. Our goal is to combine the structural information emerging from the new crystal structure with kinetic and biophysical measurements with computer modeling to achieve a detailed understanding of blocker-channel interactions. This study will investigate the intracellular and extracellular changes that occur during C-type inactivation and examine how these changes alter drug binding, accessibility and recovery. This study will provide a molecular basis for the use dependent properties of a broad class of cardiac ion channels and drugs that will further the development of safer and more effective anti-arrhythmic drug therapy.

描述（由申请人提供）：对临床应用（K+通道阻滞剂）作为抗心律失常剂的临床应用有所增加。不幸的是，已经证明HERG电流或其他缓慢延迟的整流器的减少是挑剔的，无论是在编码基因的异常还是药理学干预措施中。这使人们对快速激活的K+电流的新兴趣在心脏各个区域的心脏作用潜力的早期阶段很重要。但是，K+通道阻滞剂在每个K+通道类型的选择性方面有所不同，并显示了与K+通道的各种构象相互作用。这种构象的特定相互作用会导致通道的块程度因电刺激模式而变化。这种构型依赖性结合可能是有害的或有益的。该提议着重于研究抗心律失常药物结合与特定构象变化之间的关系，即心脏K+通道中的C型失活。与N型相比，C型失活在心脏K+通道之间的分布更广泛，并且可能是恢复，K+敏感性，PHO敏感性和药物使用依赖性等重要特性的主要决定因素。该提案的目的是阐明C型灭活如何影响心脏通道中III类药物（KV1.4，KVL.5和KV4.3）中的块和使用依赖性的复杂模式。该提议的主要假设是C型灭活涉及对细胞内孔的重排，从而导致其闭合或部分闭合。我们进一步假设S6的旋转是此过程中的一个关键事件，并且说明了细胞内闭合与S5-H5接头区域和H5-S6Linker的细胞外构象变化的耦合。我们的目标是将新晶体结构的结构信息与动力学测量和计算机建模相结合，以详细了解阻断器通道相互作用。这项研究将研究C型失活期间发生的细胞内和细胞外变化，并检查这些变化如何改变药物结合，可及性和恢复。这项研究将为广泛的心脏离子通道和药物的使用依赖性提供分子基础，这些特性将进一步发展更安全，更有效的抗心律失常药物治疗。