Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies

Eleonora Savio-Galimberti,Michael H Gollob,Dawood Darbar

doi:10.3389/fphar.2012.00124

Eleonora Savio-Galimberti, Michael H Gollob + Show 1 more

Open Access

https://doi.org/10.3389/fphar.2012.00124

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Abstract

Voltage-gated sodium channels (VGSC) are multi-molecular protein complexes expressed in both excitable and non-excitable cells. They are primarily formed by a pore-forming multi-spanning integral membrane glycoprotein (α-subunit) that can be associated with one or more regulatory β-subunits. The latter are single-span integral membrane proteins that modulate the sodium current (INa) and can also function as cell adhesion molecules. In vitro some of the cell-adhesive functions of the β-subunits may play important physiological roles independently of the α-subunits. Other endogenous regulatory proteins named “channel partners” or “channel interacting proteins” (ChiPs) like caveolin-3 and calmodulin/calmodulin kinase II (CaMKII) can also interact and modulate the expression and/or function of VGSC. In addition to their physiological roles in cell excitability and cell adhesion, VGSC are the site of action of toxins (like tetrodotoxin and saxitoxin), and pharmacologic agents (like antiarrhythmic drugs, local anesthetics, antiepileptic drugs, and newly developed analgesics). Mutations in genes that encode α- and/or β-subunits as well as the ChiPs can affect the structure and biophysical properties of VGSC, leading to the development of diseases termed sodium “channelopathies”. This review will outline the structure, function, and biophysical properties of VGSC as well as their pharmacology and associated channelopathies and highlight some of the recent advances in this field.

Highlights

In mammals, 11 genes (SCN1A–SCN11A) encode a family of nine functionally expressed voltage-gated sodium channels (VGSC; Nav1.1–Nav1.9) that share more than 50% amino acid sequence homology (Catterall et al, 2005). α-subunits encoded by these genes are organized into four homologous domains (DI–DIV), each one of which is composed of six transmembrane segments
Electrophysiological studies on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening resulting in a steadystate inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. These findings suggest that SCN4A residue 1306 is important for sodium channel inactivation (Lerche et al, 1993)
The results reported by these authors showed a clear correlation between mutations that cause gating pore current and hypokalemic periodic paralysis

Summary

INTRODUCTION

11 genes (SCN1A–SCN11A) encode a family of nine functionally expressed voltage-gated sodium channels (VGSC; Nav1.1–Nav1.9) that share more than 50% amino acid sequence homology (Catterall et al, 2005). α-subunits encoded by these genes are organized into four homologous domains (DI–DIV), each one of which is composed of six transmembrane segments. Identification of the primary structure of VGSC led to the development of the “sliding helix” (Catterall, 1986b) and the “helical screw” (Guy and Seetharamulu, 1986) models (validated by structure-function studies) to better understand how the voltage sensor operates Both models suggest that positively charged residues in segment 4 within each domain serve as the gating charges moving outward across the membrane as a consequence of membrane depolarization, initiating the activation process (Catterall, 1986a,b; Guy and Seetharamulu, 1986; Catterall et al, 2010).

Human channelopathies

Traumatic nerve injury H

Findings

Dystrophin β subunits of VGSC