Mechanisms of ion channel conduction and block

描述（由申请人提供）：本研究的长期目标是确定离子通道中选择性传导和阻断的物理机制。本提案的目的是分析离子和通道之间以及离子之间的摩擦力和由此产生的动量传递。摩擦和动量转移限制电导，有助于选择性，参与确定电流/电压图的特性，并且在通道阻断中很重要。它们是不能用平衡性质来理解的动态现象，例如离子通道的自由能景观。BK和KcsA钾通道中的摩擦和动量传递将通过扩展Stefan和麦克斯韦首先基于质量和动量守恒提出的多组分传输理论来描述。扩展的理论将提供一种手段，以链接离子电流的通道的物理特性，同时受到已知的结构信息的约束。该理论的应用将允许的传导，选择性和块的特性的特征被理解的基本物理机制，也将作为一种工具，以确定摩擦参数，不容易通过其他方法的分析。一个系统的分析将进行公开的实验钾通道电流进行测试的几个渗透性离子物种单独或混合物，以及对称和不对称的解决方案，并与不同类别的阻断剂：Na+，Mg 2+，和不同大小的糖阻断的K电流。这项研究预计将提供深入了解摩擦和动量转移的钾通道的关键功能，包括电导，钠离子的排斥，和块的作用。离子通道存在于所有细胞中，对神经元和肌肉的电活动至关重要，并参与肾脏和肠道的功能。拟议的工作旨在了解允许离子通道选择和传导离子并被各种分子阻断的物理原理和结构特征。这些信息将增加我们对离子通道功能的理解，并促进通过离子通道发挥作用的治疗剂的开发。

DESCRIPTION (provided by applicant): The long-term goal of this research is to determine the physical mechanisms of selective conduction and block in ion channels. The objective of this proposal is to analyze the frictional forces and resulting momentum transfer between ions and channel and also among ions. Friction and momentum transfer limit conductance, contribute to selectivity, are involved in determining the characteristics of current/voltage plots, and are important in channel blockade. They are dynamic phenomena that cannot be understood in terms of equilibrium properties, such as a channel's free energy landscape for ions. Friction and momentum transfer in the BK and KcsA potassium channels will be described by extending a theory of multi-component transport, first developed by Stefan and Maxwell, that is based on the conservation of mass and momentum. The extended theory will provide a means to link ionic currents to the physical properties of the channel while being constrained by known structural information. The application of the theory will allow the characteristic features of conduction, selectivity, and block to be understood in terms of basic physical mechanisms, and will also serve as a tool to determine friction parameters that are not readily available by other methods of analysis. A systematic analysis will be performed on published experimental potassium channel currents carried by several permeant ion species tested singly or in mixtures, as well as for symmetrical and asymmetrical solutions, and on K currents blocked with difference classes of blockers: Na+, Mg2+, and different sized sugars. This study is expected to provide insight into the role of friction and momentum transfer in crucial functions of potassium channels including conductance, rejection of Na ions, and block. Ion channels are found in all cells and are essential for the electrical activity of neurons and muscle and are involved in the function of kidney and intestine. The proposed work seeks to understand the physical principles and structural features that allow ion channels to select and conduct ions and to be blocked by various molecules. Such information will increase our understanding of ion channel function and should facilitate the development of therapeutic agents that act through ion channels.