The voltage sensor module in sodium channels

The mechanism by which voltage-gated ion channels respond to changes in membrane polarization during action potential signaling in excitable cells has been the subject of research attention since the original description of voltage-dependent sodium and potassium flux in the squid giant axon. The cloning of ion channel genes and the identification of point mutations associated with channelopathy diseases in muscle and brain has facilitated an electrophysiological approach to the study of ion channels. Experimental approaches to the study of voltage gating have incorporated the use of thiosulfonate reagents to test accessibility, fluorescent probes, and toxins to define domain-specific roles of voltage-sensing S4 segments. Crystallography, structural and homology modeling, and molecular dynamics simulations have added computational approaches to study the relationship of channel structure to function. These approaches have tested models of voltage sensor translocation in response to membrane depolarization and incorporate the role of negative countercharges in the S1 to S3 segments to define our present understanding of the mechanism by which the voltage sensor module dictates gating particle permissiveness in excitable cells.