Voltage-gated Na⁺channels: Potential for β subunits as therapeutic targets

Abstract

Background Voltage gated Na+ channels (VGSCs) contain a pore-forming α subunit and one or more β subunits. VGSCs are involved in a wide variety of pathophysiologies, including epilepsy, cardiac arrhythmia, Multiple Sclerosis, periodic paralysis, migraine, neuropathic and inflammatory pain, Huntington’s disease, and cancer. Increasing evidence implicates the β subunits as key players in these disorders. Objective The purpose of this report is to review the recent literature describing the multifunctional roles of VGSC β subunits in the context of their role(s) in disease. Methods An extensive review of the literature on β subunits was performed. Results/conclusion β subunits are multifunctional. As components of VGSC complexes, β subunits mediate signaling processes regulating electrical excitability, adhesion, migration, pathfinding, and transcription. β subunits may prove useful in disease diagnosis and therapy.

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

“…Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14)(15)(16)(17)(18)(19)(20)(21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactions in vitro (11). β1 also promotes neurite outgrowth in cerebellar granule neurons (CGNs) via a lipid raft mechanism involving trans homophilic cell adhesion, fyn kinase, and contactin (22,23).…”

“…7A) (11,22,25). At this stage, the AIS is not yet formed, and Na v 1.6 is proposed to conduct Na + into microdomains surrounding channel complexes in response to localized membrane depolarizations during neurite extension.…”

“…In immature CGNs lacking AIS, complexes containing Na v 1.6, β1, and contactin are present throughout the neuronal membrane in the soma, neurite, and growth cone. Localized Na + influx is necessary for β1-mediated neurite extension and migration (11,22,25). VGSC complexes along the neurite are proposed to participate in cell-cell adhesion and fasciculation (22).…”

“…VGSC β1 subunits are multifunctional molecules that modulate channel kinetics and gating, regulate channel cell surface expression, and participate in cell-cell adhesion in vitro (11). Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12,13).…”

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

“…VGSCs 3 comprise one pore-forming ␣ subunit and two ␤ subunits (␤1-␤4, encoded by Scn1b-Scn4b) that do not form the pore but play critical roles in channel subcellular localization, regulation of I Na , VGSC gene transcription, and cell adhesive interactions leading to cytoskeletal modulation, changes in cell morphology, and cellular migration (1)(2)(3).…”