The Structural Basis of Antiarrhythmic Drug Binding in Voltage-gated Ion Channels

摘要/项目摘要 心律失常影响着数百万美国人，是一种常见的病因 老年美国人的发病率和死亡率，以及医疗保健 支出。它们有很多原因，包括遗传基因突变， 电解质紊乱和药物副作用--尽管所有这些原因都有共同之处 心肌电压门控离子通道失灵。抗心律失常 药物(AAD)被广泛用于治疗房性和室性心律失常。 阻止这样的渠道，尽管目前对 在结构水平上的分子作用机制。在这项提议中，我的目标是 为了研究电压门控钠钙通道模型中的AADS，使用 广泛使用的钠通道阻滞剂AAD利多卡因和氟卡胺以及 广泛使用的钙通道阻滞剂和地尔硫卓。我将使用已建立的 电生理学和X射线结晶学技术在AAD研究中的应用 具有细菌电压门控钠和钙通道的复合体，而 致力于建立AAD结合位点的新结构模型 串联细菌通道、高阶通道和冷冻-EM方法。我 希望这些实验能够更好地理解电压门控离子 渠道生理学和帮助设计更安全、更有效的AAD 作为一种可用于治疗房室疾病的新疗法 心律不齐。

Abstract/Project Summary Cardiac arrhythmias affect millions of Americans and are a common cause of morbidity and mortality in older Americans, as well as health care expenditures. They have many causes including inherited gene mutations, electrolyte disturbances, and drug side effects—though all of these causes share the misfiring of voltage-gated ion channels in myocardium. Anti-arrhythmic drugs (AAD) are widely used to treat both atrial and ventricular arrhythmias by blocking such channels, though there is currently a limited understanding of the AAD molecular mechanism of action on a structural level. In this proposal, I aim to study AADs in model voltage-gated sodium and calcium channels, using the widely used sodium channel blocker AAD lidocaine and flecainide as well as the widely used calcium channel blocker AAD diltiazem. I will use established techniques of electrophysiology and X-ray crystallography to study AAD in complex with bacterial voltage-gated sodium and calcium channels, while working to establish new structural models of the AAD binding site using concatenated bacterial channels, higher order channels, and Cryo-EM methods. I expect these experiments to allow for a better understanding of voltage-gated ion channel physiology and aid in the design of safer and more effective AAD, as well as novel therapeutics that may be used for treatment of atrial and ventricular arrhythmias.