APPROACHING ARRHYTHMIA THERAPY THROUGH NA CHANNEL GATING

通过 NA 通道门控进行心律失常治疗

• 批准号: 3473536
• 负责人: JOSEPH RANDALL MOORMAN
• 金额: $ 11.39万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3473536
• 关键词: Xenopus; antiarrhythmic agent; arrhythmia; brain; chronic disease /disorder; congestive heart failure; coronary disorder; egg /ovum; endopeptidases; genetic manipulation; lysine; messenger RNA; phosphorylation; protein kinase C; sodium channel; sudden cardiac death; tachycardia; trypsin; voltage /patch clamp; voltage gated channel

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.

室性快速性心律失常是一个主要的健康问题，因为它们是一种 冠状动脉疾病猝死的主要原因--他们可能 以慢性充血性心力衰竭为首发症状 综合症。通常的治疗方法是阻断离子通道，特别是钠离子通道 但这些药物往往无效，有时还会有严重的 中枢神经系统副作用。这项研究的长期目标是 这项建议是为了制定一个新的框架来设计抗震墙。 心律失常药物。短期目标是(1)确定 负责其失活或关闭的NA通道分子 在持续的刺激期间，以及(2)识别在 心脏和脑钠通道之间的机制。这应该允许设计 没有中枢神经系统的有效抗心律失常药物 副作用。目标将通过两个强大的 重组DNA技术与单离子通道电流技术 大鼠脑组织III型钠通道的初步研究 在非洲爪哇卵母细胞中表达。 心脏和脑钠离子通道的作用机制不同 失活，因为心脏钠通道在去极化过程中往往会重新开放 刺激和脑钠离子通道不起作用。初步实验表明， III型钠通道分子具有两种类型的失活模式， 以及连接结构域的胞内区的选择性突变 III和IV对钠通道失活有较大影响。具体来说， 用保守的方式取代有战略意义的、积极的 赖氨酸显著加快了失活的速度，并改变了单一 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 已定义。这可以与克隆人的行为进行比较和对比 心脏钠通道，一旦它们可用。