Mechanisms of ion channel conduction and block

描述(申请人提供)：这项研究的长期目标是确定离子通道选择性传导和阻断的物理机制。这个建议的目的是分析离子与通道之间以及离子与离子之间的摩擦力和由此产生的动量传递。摩擦力和动量转移限制电导，有助于选择性，参与决定电流/电压曲线的特性，并在通道阻塞中起重要作用。它们是动态现象，不能用平衡属性来理解，比如离子的通道自由能图景。BK和KCSA钾通道中的摩擦和动量传递将通过扩展由Stefan和Maxwell首先提出的基于质量和动量守恒的多组分输运理论来描述。扩展的理论将提供一种方法，将离子电流与通道的物理属性联系起来，同时受已知结构信息的限制。该理论的应用将使人们能够从基本物理机制的角度来理解导电性、选择性和阻塞性的特征特征，并将作为确定摩擦参数的工具，而这些参数是其他分析方法所不能轻易获得的。系统地分析已发表的几种被单独或混合测试的有意义的离子携带的钾通道电流，以及对称和不对称溶液，以及被不同类别的阻滞剂：Na+，Mg2+和不同大小的糖所阻断的K电流。这项研究有望深入了解摩擦和动量转移在钾通道的关键功能中的作用，包括电导、钠离子的排斥和阻断。离子通道存在于所有细胞中，对神经元和肌肉的电活动是必不可少的，并参与肾脏和肠道的功能。这项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止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，并应有助于开发通过离子通道起作用的治疗剂。

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.