MOLECULAR PHYSIOLOGY OF CARDIAC POTASSIUM CHANNELS

该项目的目标是了解 内向整流钾通道的结构和功能。 这些通道是心脏细胞功能的中心， 参与控制动作电位波形，持续时间， 静息电位和控制细胞兴奋性。 该建议集中于K1的内向整流通道 在钾电导中表现出强烈不对称性的类， 主要分布在心脏和大脑。这个项目的目标是使用一个 综合分子、生物物理和生物化学方法， a）以下物质的功能性渗透、传导和整流性质： K1通道，B）通道多肽跨膜拓扑结构，和c） 内向整流通道的亚基组成和组装。 该项目的具体目标是： 目标1。渠道的功能特点将是 研究以确定通道孔的分子基础 性能、通道渗透和阻断、通道整流。 目标二。跨膜通道多肽的结构 将被确定。 目标3：将阐明通道的亚基组成， 将确定负责信道组装的域。 这些研究的结果将提供有关 参与内向整流器功能的分子机制 心脏和大脑的通道。对分子的理解 K1通道的结构和功能将使开发 用于治疗心血管和神经元疾病的K1通道治疗剂 疾病

The goal of this project is an understanding of the molecular basis of the structure and function of inwardly rectifying potassium channels. These channels are central to the functioning of cardiac cells where they are involved in controlling the action potential waveform, duration, resting potential and controlling cell excitability. This proposal concentrates on the inward rectifier channels of the K1 class that show strong asymmetry in potassium conductance and are found prominently in heart and brain. The goal of this project is to use an integrated molecular, biophysical and biochemical approach to investigate a) the functional permeation, conduction and rectification properties of K1 channels, b) the channel polypeptide transmembrane topology, and c) the subunit composition and assembly of inward rectifier channels. The specific aims of the project are: Aim 1. The functional characteristics of the channels will be investigated to ascertain the molecular basis for channel pore properties, channel permeation and block, and channel rectification. Aim 2. The structure of the channel polypeptide across the cell membrane will be determined. Aim 3. The subunit composition of the channels will be elucidated, and the domains responsible for channel assembly will be ascertained. The results of these studies will provide new information about the molecular mechanisms involved in the function of the inward rectifier channels in the heart and brain. An understanding of the molecular architecture and function of the K1 channels will enable the development of K1 channel therapeutic agents to treat cardiovascular and neuronal disease.