RECTIFICATION AND BLOCK OF ION CHANNEL CURRENTS

描述（改编自申请人的摘要）：拟议的研究 将检查克隆中的内在纠正机制 钾通道，利用分子生物学和 电生理学技术。 在之前的实验中，新颖的内在 克隆并表征了整流钾 (Kir) 通道，并且 多胺（精胺、亚精胺和腐胺）被鉴定为可溶性的 负责内在整顿的因素。 根据背景和 初步数据表明，多胺引起的假设是 通过 Kir 通道孔的电压依赖性阻断进行内在整流。 为了扩展初步数据并检验上述假设，四个 提出实验系列是为了解决以下问题：（1） Kir 通道阻断的多胺结构要求是什么？ (2)钾多胺嵌段涉及哪些孔隙结构 渠道？ (3) 对于渗透离子来说，Kir 孔是什么样子的？ 水？ (4)能否为理解离子建立理论基础 通道被多胺阻断？ 所提出的实验的结果， 回答上述问题，将提供详细的见解 内向矫正的基本机制，是 钾通道的功能多样性。 向内整顿是 对于调节细胞兴奋性和钾稳态至关重要 心脏、脑和其他组织。 因此，这项工作将提供 最终可能成为理性发展基础的信息 治疗心律失常、癫痫和其他疾病的疗法 细胞兴奋性障碍。

DESCRIPTION (Adapted from the applicant's abstract): The proposed study will examine the mechanisms underlying inward rectification in cloned potassium channels, utilizing a combination of molecular biological and electrophysiological techniques. In previous experiments, novel inward rectifying potassium (Kir) channels were cloned and characterized, and polyamines (spermine, spermidine and putrescine) were identified as soluble factors responsible for intrinsic rectification. Based on background and preliminary data, the hypothesis is developed that polyamines cause intrinsic rectification by voltage-dependent block of the Kir channel pore. In order to extend preliminary data and examine the above hypothesis, four experimental series are proposed to address the following questions: (1) What are the polyamine structural requirements for Kir channel blockade? (2) What pore structures are involved in polyamine block of potassium channels? (3) What does the Kir pore look like to permeating ions and water? (4) Can a theoretical basis be developed for understanding ion channel block by polyamines? The results of the proposed experiments, answering the above questions, will provide detailed insight into the fundamental mechanism of inward rectification, a critical determinant of the functional diversity of potassium channels. Inward rectification is essential for regulation of cell excitability and potassium homeostasis in cardiac, brain and other tissues. The work will therefore provide information that may ultimately underlie the development of rational therapies for the treatment of cardiac arrhythmias, epilepsy and other disorders of cell excitability.