Mechanisms of ion channel conduction and block

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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.