RECTIFICATION AND BLOCK OF ION CHANNEL CURRENTS

描述(改编自申请人的摘要)：建议的研究 将研究克隆的内向整流的潜在机制 钾通道，利用分子生物学和 电生理技术。在以前的实验中，新奇的向内 克隆并鉴定了整流钾(KIR)通道。 多胺(精胺、亚精胺和腐胺)是可溶的。 负责内在整改的因素。基于背景和 初步数据显示，假设是多胺导致 KIR通道孔的电压依赖块的本征整流。 为了扩展初步数据并检验上述假设，四个 提出了一系列实验，以解决以下问题：(1) KIR通道阻断对多胺的结构要求是什么？ (2)多胺类钾分子的孔道结构是什么？ 通道？(3)基尔孔是什么样子的渗透离子和 水？(4)能为理解离子提供理论基础吗？ 通道被多胺阻断？建议的实验结果是， 回答上述问题，将提供对 内向纠偏的基本机制，这是一个关键的决定因素 钾通道的功能多样性。向内整顿是 对细胞兴奋性和钾稳态的调节至关重要 心脏、脑和其他组织。因此，该工作将提供 最终可能成为Rational发展的基础的信息 心律失常、癫痫等疾病的治疗方法 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.