CARDIAC TRANSIENT OUTWARD CURRENT

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 不同类型心脏病患者的发病率和死亡率 疾病。最近的研究引起了人们对不良反应的广泛关注 目前用于治疗这些疾病的 I 类抗心律失常药物的效果 心律失常。这些担忧激发了人们对 III 类药物的兴趣 其作用是通过动作电位延长介导的，通常 通过封锁 K 通道。此类化合物的亲和力通常 显示出对通道构象状态的复杂依赖性。 我们对这些代理行为的有限了解受到我们的限制 了解电压相关和电压不敏感 伴随激活的转变。定量和分子 基于激活过程及其与失活耦合的模型 是阐明复杂阻塞性质的先决条件 III 类药物的作用。因此，本提案旨在 表征心脏瞬态外向 K 电流，其作用 在确定人类动作电位持续时间方面发挥着重要作用。块 瞬态向外电流似乎不太可能感应 触发活动比延迟整流器 K 通道的阻塞更有效。因为 人类和雪貂心脏 I/to 之间的独特相似性 我们的雪貂 (FK1) 和人类 (HK1) 克隆的相似性 目标是开发基于分子的生物物理模型 FK1。这项研究将结合电压钳、单通道、门控 卵母细胞和 CHO 细胞模型中 FK1 的当前和诱变研究 发展。我们将测试该模型定义的能力 封闭通道阻断化合物（4- 氨基吡啶）。该模型将包含相应的转换 单个亚基的独立运动和合作运动 激活过程中子单元之间的相互作用。在 激活将被建模为与静电激活耦合， 疏水性和变构相互作用，试图表征两者 失活的发展和恢复。最终， 阐明通道结构和功能特征可能会有所帮助 识别更新、更有效的渠道阻断剂。

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.