AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS

在初步研究中，我们已经确定了~激动剂~作用。 典型的离子通道阻滞剂。这是研究的总体目标。 在这个项目中进一步确定其背后的机制 效果，这里定义为通道门控的修改，从而导致 与药物引起的电压范围内的电流增加有关 心脏动作电位的平台期。我们迄今为止的研究 在Kv1.5介导的电流中表现出这样的效应 奎尼丁，局部麻醉剂布比卡因，以及 二十二碳六烯酸(鱼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。这个 拟议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，其产物主要是 人类延迟整流和暂态的阿尔法亚基 向外的电流。具体目标1将使用生物物理方法 来检验这样的假设，即存在特定的 激动剂效应，并将分析这些结果在高级 门禁模特。特定目标2将确定物理化学 确定激动剂作用的个别药物的性质； 这项工作可能导致~更纯净~的鉴定或合成。 激动剂。特定目标3的目标是识别分子 激动剂作用的结合部位的轨迹；工作 假设与电压传感器的相互作用(S4)或其 ~小管~有责任。减少的离子电流越来越多 被认为是导致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有重要的意义 对新药开发的影响。更广泛地说，它是 众所周知，患者的反应差异很大 抗心律失常药物；拮抗剂和迄今为止的共存- 单分子中未知的激动剂效应具有重要意义 对理解这种可变性的影响。

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.