The Voltage Sensor Module in Sodium Channels

Abstract

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.

The Selective Nav1.7 Inhibitor, PF-05089771, Interacts Equivalently with Fast and Slow Inactivated Nav1.7 Channels

“…Utilizing mutagenesis studies, we previously demonstrated that Na v 1.7-selective aryl sulfonamide inhibitors interact with the extracellular surface of the VSD region of DIV (McCormack et al, 2013;Alexandrou et al, 2016), although the precise mechanism for inhibition was not fully understood. Over the years, the use of polypeptide toxins has increased our understanding of the functional significance of the VSD of DIV in channel fast-inactivation (Catterall et al, 2007;Hanck and Sheets, 2007;Groome, 2014). Site-3 toxins, which include a-scorpion toxins and sea anemone toxins, bind to overlapping extracellular residues on the DIV S3-S4 loop, binding with highest affinity at negative membrane potentials where the channel is closed (Catterall et al, 2007).…”

Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome

“…The connection between Arg1457His and CMS affords an opportunity to better understand the mechanisms of voltage sensing and the nature of fast and slow inactivation processes in sodium channels. 39,40 There is a history of pathological Na v channel variation disrupting skeletal (eg, myotonias, periodic paralyses 23,25 ) or cardiac muscle (eg, long-QT or Brugada syndrome), 41 as well as neurons of the central nervous system and/or peripheral nervous system (eg, epilepsy, pain syndromes, congenital analgesia, anosmia, or other sensory deficits). [42][43][44][45][46][47][48] These pathogenic changes have provided a window into the basic functionality of these important channels, and in this report we add to this knowledge with the description of a residue of exceptional importance in fast inactivation, whose compromise results in a myasthenic phenotype.…”

Roles for Countercharge in the Voltage Sensor Domain of Ion Channels

“…The biophysical basis for displacement of the gating charge, and thus voltage-sensitivity, is S4 translocation in response to altered membrane potential [reviewed by (Bezanilla, 2000;Bezanilla, 2018)]. Investigations of the role of the S4 segment as the voltage sensor have employed mutagenesis including mutant cycle analysis, toxins to trap resting or activated states, thiosulfonate reagents to determine S4 residue accessibility, fluorescence measurements, and molecular dynamics simulations [reviewed by (Groome, 2014)]. Pertinent to this review, a series of investigations have supported the premise that sequential, salt-bridge (countercharge/S4 residue) interactions facilitate transitions from the resting to fully activated state of VGICs.…”