AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS

在初步的研究中，我们已经确定了一种激动剂的作用， 典型的离子通道阻断剂 这是研究的总目标 在这个项目中，进一步确定这一机制， 效应，在此定义为通道门控的修改， 药物诱导的电流增加，在电压范围内， 心脏动作电位的平台期。 我们迄今为止的研究 已经证明了对Kv1.5介导电流的这种作用， 奎尼丁，由局部麻醉剂布比卡因，并通过 二十二碳六烯酸（鱼类中主要的多不饱和脂肪酸 油）和奎尼丁对HERG介导的电流的影响。 的 拟进行的实验将使用这些药物来研究激动剂的作用 在Kv1.5、Herge和Kv4.3上，这些基因的产物是主要的 人延迟整流和瞬时整流的α亚单位 外向电流 具体目标1将使用生物物理方法 为了检验存在特异性结合位点的假设， 激动剂的作用，并将分析这些结果方面的先进的 门控模型。 具体目标2将确定物理化学 决定激动剂作用的单个药物的性质; 这项工作可能导致鉴定或合成更纯的 激动剂具体目标3的目标是确定 激动剂作用的结合位点的位点;工作位点 假设与电压传感器（S4）或其 ~canaliculus~负责。减少的离子电流越来越多地 被认为是心律失常的潜在因素，因此进一步 对这种激动剂效应的理解应该是重要的 对新药开发的影响。 更一般地说， 众所周知，患者对以下问题的反应差异很大： 抗心律失常药物;拮抗剂和迄今为止的共存- 在单分子中未被识别的激动剂作用具有重要的 对理解这种变化的影响。

In preliminary studies, we have identified an ~agonist~ action of prototypical ion channel blockers. It is the overall goal of studies in this Project to further determine mechanisms underlying this effect, defined here as a modification of channel gating that leads to a drug-induced increase in current in the voltage range of the plateau phase of the cardiac action potential. Our studies to date have demonstrated such an effect on Kv1.5-mediated currents by quinidine, by the local anesthetic bupivacaine, and by docosahexaenioc acid (the main polyunsaturated fatty acid in fish oils) and on HERG-mediated currents by quinidine. The experiments proposed will use these agents to study agonist effects on Kv1.5, Herge, and Kv4.3, genes whose products are major alpha-subunits underlying human delayed rectifier and transient outward currents. Specific Aim 1 will use biophysical approaches to test the hypothesis that a specific binding site exits for the agonist effect, and will analyze these results in terms of advanced gating models. Specific Aim 2 will identify physicochemical properties of individual drugs that determine the agonist action; this work may lead to identification or synthesis of ~purer~ agonist. The goal of Specific Aim 3 is to identify the molecular locus of a binding site for the agonist effect; the working hypothesis is that an interaction with the voltage sensor (S4) or its ~canaliculus~ is responsible. Reduced ion current is increasingly recognized as a potential contributor to arrhythmias, so further understanding of this agonist effect should have important implications for new drug development. More generally, it is well-recognized that patients vary widely in their responses to antiarrhythmic drugs; the coexistence of antagonist and heretofore- unrecognized agonist effect in single molecules has important implications for understanding this variability.