MOLECULAR BASIS OF TRANSIENT OUTWARD CURRENT ACTIVATION AND INACTIVATION

瞬态外向电流激活和失活的分子基础

• 批准号: 6273041
• 负责人: HAROLD CARL STRAUSS
• 金额: $ 25.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-26 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273041
• 关键词: CHO cells; action potentials; allosteric site; aminopyridines; antiarrhythmic agent; arrhythmia; conformation; congestive heart failure; disease /disorder model; electrophysiology; ferrets; heart pharmacology; hydropathy; ionic bond; membrane structure; model design /development; molecular pathology; potassium channel; site directed mutagenesis; voltage gated channel

MOLECULAR BASIS FOF TRANSIENT OUTWARD CURRENT ACTIVATION AND INACTIVATION . Atrial and ventricular arrhythmias represent a significant cause of morbidity and mortality in patients with congestive heart failure. Recent studies have raised widespread concern about the averse effects of current Class I antiarrhythmic drugs used to treat these arrhythmias. These concerns have spurred interest in Class III agents whose action is mediated through action potential prolongation, usually via blockade of K+ channels. The affinity of sch compounds typically shows a complex dependency upon the conformational state of the channel. Our limited understanding of the action of these agents is limited by our understanding of the voltage dependent and voltage insensitive transitions which accompany activation. A quantitative and molecularly based model of the activation process and its coupling to inactivation is a prerequisite for elucidating the nature of the complex blocking action of Class III agents. Therefore, this proposal seeks to characterize the cardiac transient outward K+ current, Ito, which plays a significant role in determining human action potential duration. Block of I to appears to e less likely to induce triggered activity than block of delayed rectifier K+ channels. Because of the unique similarities between the human and ferret cardiac I to and the near identity of our ferret (FK1) and the human (HK1) clone, our objective will be to develop a molecularly based biophysical model of Ito/FK1. This study will combine voltage-clamp, single channel, studies of I to in isolated ferret ventricular myocytes for model development. We will test the ability of this model to define the mechanism of action of a closed channel blocking compound (4-aminopyridine). Inactivation will be modeled as coupled to action to characterize both the development of and recovery from inactivation. Ultimately, elucidation of channel structural and functional features may help identify newer and more efficacious channel blockers.

瞬态外向电流激活和失活的分子基础 。 房性心律失常和室性心律失常是导致心律失常的重要原因 充血性心力衰竭患者的发病率和死亡率。 最近的 研究引起了人们对当前的不利影响的广泛关注 I类抗心律失常药物用于治疗这些心律失常。 这些 担忧激起了人们对 III 级特工的兴趣，其行动是经过调解的 通过动作电位延长，通常通过阻断 K+ 通道。 sch 化合物的亲和力通常表现出复杂的依赖性 通道的构象状态。 我们的了解有限 这些药剂的作用受到我们对电压的理解的限制 伴随激活的依赖和电压不敏感的转变。 活化过程的定量和分子模型 其与失活的耦合是阐明其性质的先决条件 III 类药物的复杂阻断作用。 因此，这 该提案旨在描述心脏瞬态外向 K+ 电流的特征， 伊藤，在确定人类动作电位方面发挥着重要作用 期间。 I 至 e 的块似乎不太可能诱发触发 活性高于延迟整流器 K+ 通道的阻断。 因为 人类和雪貂心脏 I 之间的独特相似之处 我们的雪貂 (FK1) 和人类 (HK1) 克隆的身份，我们的目标将 开发基于分子的 Ito/FK1 生物物理模型。 这项研究 将结合电压钳、单通道、I 的研究以隔离 用于模型开发的雪貂心室肌细胞。 我们将测试 该模型能够定义封闭通道的作用机制 阻断化合物（4-氨基吡啶）。 失活将被建模为 结合行动来描述发展和恢复的特征 失活。 最终阐明通道的结构和功能 这些功能可能有助于识别更新且更有效的通道阻断剂。