The Role of Non-pore-Forming β Subunits in Physiology and Pathophysiology of Voltage-Gated Sodium Channels

Abstract

Voltage-gated sodium channel β1 and β2 subunits were discovered as auxiliary proteins that co-purify with pore-forming α subunits in brain. The other family members, β1B, β3, and β4, were identified by homology and shown to modulate sodium current in heterologous systems. Work over the past 2 decades, however, has provided strong evidence that these proteins are not simply ancillary ion channel subunits, but are multifunctional signaling proteins in their own right, playing both conducting (channel modulatory) and nonconducting roles in cell signaling. Here, we discuss evidence that sodium channel β subunits not only regulate sodium channel function and localization but also modulate voltage-gated potassium channels. In their nonconducting roles, VGSC β subunits function as immunoglobulin superfamily cell adhesion molecules that modulate brain development by influencing cell proliferation and migration, axon outgrowth, axonal fasciculation, and neuronal pathfinding. Mutations in genes encoding β subunits are linked to paroxysmal diseases including epilepsy, cardiac arrhythmia, and sudden infant death syndrome. Finally, β subunits may be targets for the future development of novel therapeutics.

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

“…The extracellular Ig domain of β1 facilitates adhesive interactions, including trans homophillic interaction with β1 molecules on neighboring cells (Calhoun and Isom, 2014). In order to assess this intercellular adhesion function, as well as to create an assay model for identification of β1 adhesion antagonists, we quantified intercellular junctional resistance changes in cells heterologously overexpressing β1 (1610 β1OX) using electric cell-substrate impedance sensing (ECIS).…”

Sodium channel blockers: a patent review (2010 – 2014)

“…The inventors tested > 250 compounds and they showed IC 50 values between 0.03 and > 20 µM. Some molecules were also tested in vivo for their antinociceptive activity, and those reported in Figure 2 (compounds [8][9][10][11][12][13] produced a statistically significant increase in pain withdrawal threshold, when administered at 30 mg/Kg per os in the Seltzer model of neuropathic pain.…”

“…Moreover each sodium channel subtype is accompanied by one or more b subunit. These are not involved in pore formation but can modulate the properties of a subunit, participating into the modulation of sodium currents and covering a prominent role in migration and cell surface expression of VGSCs [6][7][8][9][10][11][12][13].…”

Surface dynamics of voltage-gated ion channels

“…28,31,57,58 Although, the a subunit is sufficient for expression of functional channels, auxiliary b subunits modulate the gating, voltage-dependence and kinetics of the channel, as well as its localization and interaction with intra-and extracellular scaffolds. 19,23,31 In central neurons, Na v 1.1-1.3 and Na v 1.6 are the primary sodium channel isoforms, while Na v 1.7-1.9 are expressed predominantly in peripheral neurons. 56,133,142 Additionally, sodium channels are expressed in non-excitable cells where they can serve non-canonical functions.…”