Mechanisms of ion channel conduction and block

离子通道传导和阻断机制

• 批准号: 7353978
• 负责人: WOLFGANG F NONNER
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7353978
• 关键词: Ants; Behavior; Cells; Characteristics; Chemical Engineering; Chin; Class; Classification; Condition; Coupled; Coupling; Data; Dependence; Development; Diffusion; Electrostatics; Equilibrium; Free Energy; Friction; Generic Drugs; Goals; Hodgkin Disease; Intestines; Ion Channel; Ion Transport; Ions; Isotopes; Kinetics; Length; Link; Literature; Location; Measurement; Measures; Melanocytic nevus; Membrane Potentials; Metabolic; Modeling; Mole the mammal; Motion; Muscle; Neurons; Pathway interactions; Pattern; Personal Satisfaction; Physics; Physiological; Potassium Channel; Property; Publishing; Range; Renal function; Research; Role; Side; Site; Sodium Chloride; Solutions; Standards of Weights and Measures; Structure; System; Tail; Techniques; Testing; Therapeutic Agents; Thinking; Time; Vestibule; Work; Writing; base; chemical kinetics; computer code; cost; driving force; experience; fascinate; innovation; insight; molecular dynamics; nanometer; nanosecond; particle; physical property; size; sugar; theories; tool; voltage

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.

描述（由申请人提供）：这项研究的长期目标是确定离子通道中选择性传导和阻塞的物理机制。该提案的目的是分析离子与渠道之间以及离子之间的摩擦力和产生的动量转移。摩擦和动量转移极限电导有助于选择性，参与确定电流/电压图的特征，并且在通道阻滞中很重要。它们是动态现象，无法从平衡特性（例如一个通道的自由能景观）来理解。 BK和KCSA钾通道中的摩擦和动量转移将通过扩展由Stefan和Maxwell首先开发的多组分传输理论来描述，该理论基于质量和动量的保护。扩展的理论将提供一种将离子电流与通道的物理特性联系起来的手段，同时受到已知结构信息的约束。该理论的应用将允许从基本物理机制来理解传导，选择性和块的特征，并且还将作为确定其他分析方法不容易获得的摩擦参数的工具。将对单独或混合物中的几种渗透离子物种以及对称和不对称溶液进行的几种渗透离子物种携带的已发表的实验性钾通道电流进行系统分析，并在差异类别中封闭的差异类别：Na+，Mg2+，MG2+和不同大小的糖。预计这项研究将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，拒绝NA离子和阻滞。离子通道都在所有细胞中都发现，对于神经元和肌肉的电活动至关重要，并且参与了肾脏和肠的功能。拟议的工作旨在理解允许离子通道选择和进行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，并应促进通过离子通道起作用的治疗剂的发展。