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: 5214276
• 负责人: HAROLD C STRAUSS
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5214276
• 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.

瞬态外电流激活与失活的分子基础 . 房性和室性心律失常是导致 充血性心力衰竭患者的发病率和死亡率。 最近 研究已经引起了人们对当前的不利影响的广泛关注。 用于治疗这些心律失常的I类抗心律失常药物。 这些 人们对III类药物的关注引起了人们对III类药物的兴趣， 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显示出对亲合力的复杂依赖性。 通道的构象状态。 我们对宇宙的有限理解 这些药剂的作用受到我们对电压的理解的限制， 依赖的和电压不敏感的转变伴随激活。 活化过程的定量和基于分子的模型， 它与失活的偶联是阐明 III类药物的复杂阻断作用。 因此本 提案寻求表征心脏瞬时外向K+电流， Ito在决定人体动作电位中起着重要作用 持续时间 I to阻滞似乎不太可能诱发触发性 延迟整流钾离子通道的阻断。 因为 人类和雪貂心脏之间的独特相似性 我们的雪貂（FK 1）和人类（HK 1）克隆的身份，我们的目标将 开发一个基于分子的Ito/FK 1生物物理模型。 本研究 将联合收割机电压钳、单通道、I研究与隔离 用于模型开发的雪貂心室肌细胞。 我们将测试 该模型定义封闭通道作用机制的能力 封闭化合物（4-氨基吡啶）。 失活将建模为 结合采取行动， 失活 最后，阐明了通道的结构和功能 特征可以帮助识别更新和更有效的通道阻断剂。