This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Voltage gated ion channels open or close in response to changes in membrane potential. The general molecular features of selectivity and voltage gating in ion channels have been worked out using electrophysiological and molecular biological methods. Selectivity arises from a discrete selectivity pore identifiable by signature sequence motifs. Voltage gating comes primarily from arginines in S4, the fourth TM segment. Structural studies have greatly enhanced our understanding of these features. In the case of K+ channels, they have led to an understanding of the stereo-chemical, and electrostatic details of selectivity. Currently there are no analogous studies and no stereo-chemical understanding of Na+ channels. The most promising route to such information is through structural studies of bacterial channels, and the only known voltage-gated bacterial Na+ channels are members of the NaChBac family. These channels exhibit many of the properties of more complex mammalian voltage-dependent sodium and calcium channels, but are much simpler and more amenable to structural studies.
The aims of this proposal are to complete the structure and determine the mechanisms of sodium selectivity and anti-arrhythmia drug binding in a family of sodium-selective ion channels. Methods for immobilizing inherently flexible molecules will be developed to aid in crystallization. The long-term impact of this work is a better understanding of the mechanism of Sodium Channels leading to novel methods of modulating these channels. Toward this end we will determine the stereo-chemical details of dihydropyridine drug binding, with a long-term goal being to improve treatment of Sodium Channel dysfunctions. Inheireted Na+ channelopathies result in cardiac ahrythmias and epilepsy, while acquired Na+ channelopathies (usually through injury) contribute to chronic pain and multiple schlerosis.
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