RECTIFICATION AND BLOCK OF ION CHANNEL CURRENTS

描述（申请人提供）：离子通道调节许多组织的兴奋性，多种疾病是由离子通道基因突变引起的。该项目主要研究一类钾离子通道，即向内整流（Kir）通道。迄今为止，已经确定可溶性细胞质多胺在强内向整流器中引起内向整流，以及多胺块的位置和通道内的门控。现在，大量的初步数据使我们对通道渗透、阻滞和门控的分子细节有了新的假设。这些假设将在拟议的实验中进行严格检验，利用由重组细菌Kir通道同源物组成的独特模型系统，适用于物理，生化和电生理技术的组合，以及分子建模来定义Kir通道功能的物理基础。公共卫生相关性：相关性。基尔通道对许多组织和器官的功能至关重要。Kir通道突变可引起心律失常、癫痫、糖尿病等细胞兴奋性紊乱。在了解这些Kir通道如何运作，它们如何被阻断和门控的过程中，这项工作将提供基本信息，解释Kir通道如何起作用，从而为开发治疗这些疾病的合理疗法提供帮助。

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.