RECTIFICATION AND BLOCK OF ION CHANNEL CURRENTS

描述(申请人提供)：离子通道调节许多组织中的兴奋性，多种疾病是由离子通道基因突变引起的。本项目主要研究一类钾离子通道，即内向整流(KIR)通道。到目前为止，已经确定了可溶性细胞质多胺引起强大的内向整流器的内向整流，以及通道内多胺阻断和门控的位置。大量的初步数据现在引导我们提出关于通道渗透、阻断和门控的分子细节的新假设。这些假说将在拟议的实验中进行严格的检验，利用一个独特的模型系统，该系统由重组细菌KIR通道同源基因组成，符合物理、生化和电生理技术的组合，结合分子建模来定义KIR通道功能的物理基础。公共卫生相关性：相关性。KIR通道对许多组织和器官的功能至关重要。KIR通道的突变可导致心律失常、癫痫、糖尿病和其他细胞兴奋性障碍。为了了解这些KIR通道是如何运作的，它们如何被阻断和门控，这项工作将提供基本信息，解释KIR通道如何发挥作用，从而为这些疾病的治疗提供合理的治疗方法。

DESCRIPTION (provided by applicant): Ion channels regulate excitability in many tissues, and multiple diseases result from mutations of ion channel genes. This project is focused on one class of potassium channels, the inward rectifying (Kir) channels. To date, it has been determined that soluble cytoplasmic polyamines cause inward rectification in strong inward rectifiers, together with the location of polyamine block and gating within the channel. Extensive preliminary data now lead us to novel hypotheses regarding the molecular details of channel permeation, block, and gating. These hypotheses will be critically examined in the proposed experiments, utilizing a unique model system consisting of recombinant bacterial Kir channel homolog, amenable to a combination of physical, biochemical and electrophysiological techniques, together with molecular modeling to define the physical basis of Kir channel function. PUBLIC HEALTH RELEVANCE: Relevance. Kir channels are critical for the function of many tissues and organs. Mutations of Kir channels can cause cardiac arrhythmias, epilepsies, diabetes and other disorders of cell excitability. In understanding how these Kir channels operate, how they can be blocked and gated, this work will provide fundamental information that will explain how Kir channels function and thereby provide for the development of rational therapies for treatment of these diseases.