K+ CHANNELS--STRUCTURE/FUNCTION RELATION & PHARMACOLOGY

我们研究的长期目标是了解心脏离子是如何 经络受药理作用和病理调节 条件。这些信息对于设计有效的 抗心律失常药物与心律失常的有效治疗 在病理条件下。实现这一目标的关键是 深入理解结构与功能的关系 心脏离子通道。分子克隆和分子生物学的研究进展 突变技术使我们能够将克隆的通道关联起来 在心脏中有天然通道的亚基，并操纵它们的 初级序列以特定的方式使渠道之间的关系 可以推断出其结构和功能。本应用程序的重点是 是中的快速(Ikr)和慢(Iks)延迟整流K通道 心。Ikr和iKs是动作电位的主要决定因素 心肌细胞的时程(时程)。它们在维护国家安全方面的重要性 正常的心脏电活动与它们独特的门控有关 属性。IKR的快速失活和再激活过程 在其I-V中引起向内整流。这有助于保持 第二阶段处于正平台阶段，但仍有足够的外向电流 三相复极化。另一方面，缓慢的激活和 IKs失活过程是动作电位失活的重要机制 通过心率的变化进行调节。这些缓慢的浇注过程 与IKS的两个亚基KvLQT1和KvLQT1之间的相互作用有关 发出嘶嘶声。IKr和iKs也是K通道调制器的重要目标。 关于目前的行动机制和地点的信息 IKR和IKS上可用的K通道调制器可能有助于设计新的 抗心律失常药物。我们建议使用克隆的K通道亚基作为 模型(用于IKR的HERG和用于IKS的KvLQT1/HISK)，并结合站点- 定向诱变和电生理技术研究 结构-功能关系和药物-通道相互作用。四 提出了具体目标：(1)研究中国经济增长的结构基础 HERG独特的门控行为，(2)研究阿齐米特的作用机制 S对HERG的激动剂和拮抗剂作用，(3)研究HERG的结构域 KvLQT1参与与hisk的相互作用，(4)研究其机制 阿齐米德和奎尼丁对iks的不同作用。它是 预计这些研究的结果将改善我们的 了解IKR和IKS的功能和调节，以及 对阿齐米特和奎尼丁的研究将提供深远的 K通道上药物作用的含义。

The long-term objective of our research is to understand how cardiac ion channels are modulated by pharmacological agents and by pathological conditions. This information is critical for the design of efficacious antiarrhythmic agents and effective management of cardiac arrhythmias under pathological conditions. The key to achieving this objective is to have a thorough understanding of the structure-function relationship of cardiac ion channels. The advance of molecular cloning and mutagenesis techniques has allowed us to correlate cloned channel subunits with native channels in the heart, and to manipulate their primary sequences in specific ways so that the relation between channel structure and function can be deduced. The focus of this application is the rapid (IKr) and slow (IKs) delayed rectifier K channels in the heart. IKr and IKs are the primary determinants of action potential duration (APD) in cardiac myocytes. Their importance in maintaining the normal cardiac electrical activity is related to their unique gating properties. The fast inactivation and reactivation processes of IKr cause an inward rectification in its I-V. This helps maintain a positive plateau phase during phase 2 and yet sufficient outward current for phase 3 repolarization. On the other hand, the slow activation and deactivation processes of IKs are an important mechanism for APD regulation by changes in the heart rate. These slow gating processes are related to the interactions between two subunits of IKs: KvLQT1 and hIsK. IKr and IKs are also important targets for K channel modulators. Information about the mechanisms and sites of actions of currently available K channel modulators on IKr and IKs may aid the design of new antiarrhythmic drugs. We propose to use cloned K channel subunits as a model (hERG for IKr and KvLQT1/hIsK for IKs), and combine site- directed mutagenesis and electrophysiological techniques to study the structure-function relationship and drug-channel interactions. Four Specific Aims are proposed: (1) To study the structural basis for the unique gating behavior of hERG, (2) To study the mechanisms of azimilide s agonist and antagonist actions on hERG, (3) To study the domains of KvLQT1 involved in interactions with hIsK, (4) To study the mechanisms of differential actions of azimilide and quinidine on IKs. It is anticipated that results from these studies will improve our understanding of the function and modulation of IKr and IKs, and the studies on azimilide and quinidine should provide far-reaching implications for drug actions on K channels.