CARDIAC TRANSIENT OUTWARD CURRENT

心脏瞬态外向电流

• 批准号: 2230535
• 负责人: HAROLD CARL STRAUSS
• 金额: $ 21.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2230535
• 关键词: CARDIAC; TRANSIENT; OUTWARD; CURRENT

Atrial and ventricular arrhythmias represent a significant cause of morbidity and mortality in patients with different forms of heart disease. Recent studies have raised widespread concern about the adverse effects of current Class I anti-arrhythmic 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 such 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 a cardiac transient outward K+ current which plays a significant role in determining human action potential duration. Block of transient outward currents appears to be 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 FK1. This study will combine voltage-clamp, single channel, gating current and mutagenesis studies of FK1 in oocytes and CHO cells 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). This model will incorporate transitions will correspond to both independent movement of single subunits and cooperative interactions between subunits during the activation process. In activation will be modeled as coupled to activation by electrostatic, hydrophobic and allosteric interactions in an effort 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.

房性和室性心律失常是导致 不同类型心脏病患者的发病率和死亡率 疾病最近的研究已经引起了广泛的关注， 目前用于治疗这些疾病的I类抗疟疾药物的作用 心律不齐这些担忧激发了人们对III类药物的兴趣 其作用通过动作电位延长介导，通常 通过阻断K+通道。这些化合物的亲和力通常 显示了对通道构象状态的复杂依赖性。 我们对这些代理人的行动的有限理解受到我们的限制。 了解电压依赖和电压不敏感 伴随激活的过渡。一个定量和分子 活化过程及其与失活的耦合 是阐明复杂阻塞性质的先决条件 第三类代理人。因此，这项建议旨在 表征心脏瞬时外向K+电流， 在确定人体动作电位持续时间方面具有重要作用。块 瞬时外向电流似乎不太可能诱导 延迟整流钾离子通道的阻断。因为 人类和雪貂心脏I/to之间的独特相似性， 我们的雪貂（FK 1）和人类（HK 1）克隆的相似性，我们的 目标将是开发一个基于分子的生物物理模型， FK1本研究将联合收割机电压钳、单通道、门控 用于模型的卵母细胞和CHO细胞中FK 1的当前和诱变研究 发展我们将测试此模型定义 封闭通道阻断化合物（4- 氨基吡啶）。该模型将包含过渡， 单个亚基的独立运动和协同运动 在激活过程中子单元之间的相互作用。在 激活将被建模为通过静电耦合到激活， 疏水和变构相互作用，以表征 失活的发展和从失活中恢复。最后， 通道结构和功能特征的阐明可能有助于 识别更新和更有效的通道阻滞剂。