RECTIFICATION AND BLOCK OF ION CHANNEL CURRENTS

描述（改编自申请人摘要）：拟定研究 将研究克隆的内向整流的机制， 钾通道，利用分子生物学和 电生理技术。 在以前的实验中， 整流钾（Kir）通道的克隆和表征， 多胺（精胺、亚精胺和腐胺）被鉴定为可溶性的 负责固有整流的因素。 根据背景和 根据初步数据，提出了多胺引起 通过Kir通道孔的电压依赖性阻断的内在整流。 为了扩展初步数据并检验上述假设， 提出了一系列实验来解决以下问题：（1） Kir通道阻断剂对多胺的结构要求是什么？ (2)钾的多胺嵌段涉及哪些孔结构 渠道？ (3)基尔孔是什么样子的渗透离子和 水吗 (4)能否为理解离子发展出一个理论基础 多胺通道阻滞剂 所提出的实验的结果， 回答上述问题，将提供详细的见解， 内向整流的基本机制，一个关键的决定因素， 钾离子通道的功能多样性 内向整流是 对调节细胞兴奋性和钾稳态至关重要， 心脏、大脑和其他组织。 因此，这项工作将提供 这些信息最终可能会成为理性发展的基础。 用于治疗心律失常、癫痫和其他疾病的疗法 细胞兴奋性紊乱。

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.