APPROACHING ARRHYTHMIA THERAPY THROUGH NA CHANNEL GATING

室性快速性心律失常是一个主要的健康问题，因为它们是一个 冠状动脉疾病猝死的主要原因-其中他们可能 是慢性充血性心力衰竭的第一个表现 综合征通常的治疗方法是阻断离子通道，特别是钠离子通道。 渠道，但药物往往无效，有时有严重的 中枢神经系统副作用研究的长期目标是 这一建议是为设计反 麻醉药。短期目标是（1）确定 钠通道分子负责其失活，或关闭 在持续刺激期间，以及（2）识别 心脏和大脑Na通道之间的机制。这将使设计 没有中枢神经系统的有效抗癫痫药物 副作用.这些目标将通过两个强大的 重组DNA技术和单离子通道电流技术 分析，以研究，最初，III型钠通道从大鼠脑 在非洲爪蟾卵母细胞中表达。 心脏和大脑Na通道具有功能上不同的机制， 失活，因为心脏Na通道在去极化过程中倾向于重新开放。 刺激和脑Na通道不起作用。试点实验表明， III型Na通道分子具有两种类型的失活模式， 细胞内区域连接结构域的选择性突变 III和IV对Na通道失活有很大影响。具体地说， 保守取代策略性放置，带正电荷 赖氨酸能显著加快失活速率， 通道动力学参数 通过研究更多的突变在这一领域的影响， 分子，脑钠通道失活的分子机制应该是 定义了这可以与克隆的行为进行比较和对比。 心脏钠通道，一旦它们可用。

Ventricular tachyarrhythmias are a major health concern because they are a chief cause of sudden death in coronary artery disease - of which they may be the first manifestation - and chronic congestive heart failure syndromes. The usual therapy is blockade of ion channels, particularly Na channels, but the drugs are often ineffective and sometimes have severe central nervous system side effects. The long term goal of the research in this proposal is to develop a new framework for the design of anti- arrhythmic drugs. The short term goals are to (1) identify the parts of the Na channel molecule that are responsible for its inactivation, or closing during a sustained stimulus, and (2) to identify differences in the mechanism between cardiac and brain Na channels. This should allow design of effective antiarrhythmic drugs which do not have central nervous system side effects. The goals will be accomplished using the two powerful techniques of recombinant DNA technology and single ion channel current analysis to study, initially, the type III Na channel from rat brain expressed in Xenopus oocytes. Cardiac and brain Na channels have functionally different mechanisms of inactivation, as cardiac Na channels tend to reopen during a depolarizing stimulus and brain Na channels do not. Pilot experiments have shown that the type III Na channel molecule has both types of inactivation patterns, and that selective mutations in the intracellular region linking domains III and IV have large effects on Na channel inactivation. Specifically, conservative substitutions for strategically placed, positively charged lysines remarkably speed up the rate of inactivation and alter single channel kinetic parameters. Through study of the effects of more mutations in this area of the molecule, a molecular mechanism for brain Na channel inactivation should be defined. This may be compared and contrasted with the behavior of cloned cardiac Na channels, once they are available.