Voltage-gated channels are membrane proteins that contain three crucial structural elements: an ion conduction pore domain (PD) that can distinguish K+ from Na+ and Ca2+ ions;a gate within the PD that minimizes the flow of ions in the closed state;and voltage-sensing domains (VSD) that detect changes in membrane voltage and trigger opening and closing of the gate. A fundamental experimental problem is the difficulty of capturing critical atomic details of VSDs in membranes by crystallography. This program project (Stephen White, Director) is designed to obtain critical structural information about VSDs in fluid lipid bilayers through the concerted use of specific deuteration, neutron diffraction, neutron reflectivity, and molecular dynamics simulations. The Program consists of six closely interlocked Projects and an important collaboration: Core A. Administrative Core. Stephen White, PI. This core provides administrative support for the entire Program. Core B. Neutron Scattering Core. Stephen White, PI. The neutron Core provides technical and training support for neutron diffraction/reflectivity measurements that will be carried out at the NIST Center for Neutron Research. Core C. Organic Synthesis Core, Richard Chamberlin, PI. The Organic Synthesis Core will provide novel specifically deuterated compounds, such as lipids and amino acids, and will carry out semi-syntheses of VSDs and channels. It will be located at UC Irvine. Project 1. Molecular Dynamics Simulations of Channels and Voltage Sensor Domains. Douglas Tobias, PI. Located at UC Irvine, this project is devoted to MD simulations that underlie-and inspire-most of the experimental work in projects 2 and 3. Project 2. Neutron Diffraction Studies of Voltage Sensor Molecules in Lipid Bilayers. Stephen White, PI. The experiments are directed toward a structural understanding of the interactions of the KvAP VSD in bilayers, the interaction of the KvAP S4 helix with lipids in multilamellar bilayers, and the disposition of the VSD-blocking toxin VSTxl toxin in bilayers. Project 3. Structural Studies of Voltage-Gated Potassium Channels as a Function of Transmembrane Electrochemical Potential. J. Kent Blasie, PI. Located at the University of Pennsylvania, this project is directed toward incorporating VSDs and whole potassium channels into single, tethered lipid bilayers and to observe by time-resolved x-ray reflectivity and neutron reflectivity structural changes in the sensors and channels induced by transmembrane electrochemical potentials. Collaboration. Potassium Channel Biophysics. Kenton Swartz, PI. Dr. Swartz's laboratory at the NINDS has an influential research program devoted to the mechanism of voltage gated ion channels. His work focuses directly on the molecular basis of voltage sensor domains and their interactions with VSD-blocking toxins.
This Program Project investigates how ion channels gate the flow of ions across nerve, muscle, and cardiac cells in response to changes in voltage across their cell membranes. These voltage changes, called action potentials, are the means by which nerve, muscle, and cardiac cells communicate with each other. Many neuromuscular and cardiac diseases arise from defects in the way action potentials are produced. Results from this Program will help us understand the origin of such diseases.
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