Basic Mechanisms of Ion Channel Function

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DESCRIPTION: This research is focused on understanding the basic chemical mechanisms by which K+ channel proteins work. Near atomic-resolution structures are emerging for ion channels and for isolated domains thereof, and this work will exploit our new knowledge of these structures in asking questions about K+ channel mechanisms. In particular, the proposed work is aimed at two K+ channels - the bacterial channel KcsA, which has produced unprecedented insight into the chemistry of ion selectivity, and Shaker, a well-studied "Kv"-type channel representative of many homologous channels in the nervous system. KcsA may be expressed at high levels and studied in biochemically defined, purified systems. We will lay out the basic ion permeation properties of KcsA by recording single channels in reconstituted membranes. Using this system, we will examine the reasons for the odd shape of the permeation pathway, focusing particularly on the electrostatics of ion transport. We will use magnetic resonance methods to directly measure binding of ions to the pore. In addition, we will attempt to understand the molecular architecture of Shaker K+ channels by a combination of techniques designed to measure distances between specific regions of the channel. This research is not directed towards any particular disease-related problem; it is the central roles that K+ channels play in virtually all human physiology that make this basic research relevant to human health in general.