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，离子通道基因突变导致多种疾病。该项目的重点是一类钾通道，内向整流（Kir）通道。到目前为止，已经确定，可溶性细胞质多胺引起内向整流强内向整流，连同多胺块和通道内的门控的位置。广泛的初步数据，现在导致我们的新的假设，关于通道渗透，块和门控的分子细节。这些假设将在拟议的实验中进行严格审查，利用一个独特的模型系统组成的重组细菌Kir通道同源物，服从物理，生物化学和电生理技术的组合，连同分子建模，以定义Kir通道功能的物理基础。公共卫生：相关性。Kir通道对于许多组织和器官的功能至关重要。Kir通道的突变可引起心律失常、癫痫、糖尿病和其他细胞兴奋性障碍。在了解这些Kir通道如何运作，它们如何被阻断和门控时，这项工作将提供基本信息，解释Kir通道如何发挥作用，从而为治疗这些疾病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.