MOLECULAR BASIS OF TRANSIENT OUTWARD CURRENT ACTIVATION AND INACTIVATION

分子基础FOF瞬时外向电流的激活与失活 。房性和室性心律失常是 充血性心力衰竭患者的发病率和死亡率。近期 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 担忧激起了人们对其行动经过调解的III类特工的兴趣 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表现出对 渠道的构象状态。我们对世界的有限了解 这些药剂的作用受到我们对电压的理解的限制 伴随激活而来的依赖和电压不敏感的转变。 激活过程的定量和基于分子的模型和 它与失活的偶联是阐明其本质的先决条件 三类药物复杂的阻断作用。因此，这 该提案试图描述心脏瞬间外向K+电流， Ito，它在确定人类行动潜力方面发挥着重要作用 持续时间。阻断I-to似乎不太可能触发诱导 激活比阻断延迟整流钾通道。因为 人和雪貂心脏Ito和邻近的独特相似之处 我们的雪貂(FK1)和克隆人(HK1)的身份，我们的目标是 将建立基于分子的ITO/FK1生物物理模型。本研究 将电压钳位与单通道相结合，研究Ito中的隔离 用于模型开发的雪貂心室肌细胞。我们将测试 该模型能够定义闭合渠道的作用机制 封闭化合物(4-氨基吡啶)。停用将被建模为 同时采取行动，描述……的发展和复苏 失活。最终，阐明通道的结构和功能 这些特征可能有助于识别更新、更有效的通道阻滞剂。

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.