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滞的物理机制。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。摩擦和动量传递限制电导，有助于选择性，参与决定电流/电压图的特性，并且在通道封锁中很重要。它们是动态现象，不能用平衡特性来理解，比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。扩展理论将提供一种方法，将离子电流与通道的物理性质联系起来，而不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传导、选择性和块的特征，并将作为确定其他分析方法难以获得的摩擦参数的工具。将对已发表的实验钾通道电流进行系统分析，该电流由几种渗透离子单独或混合进行测试，以及对称和不对称溶液，以及由不同类型的阻滞剂（Na+， Mg2+和不同大小的糖）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、Na离子的排斥和阻滞。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。提出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，并将促进通过离子通道起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.