An Emerging Role for Voltage-Gated Na+ Channels in Cellular Migration: Regulation of Central Nervous System Development and Potentiation of Invasive Cancers

Abstract

Voltage-gated Na⁺ channels (VGSCs) exist as macromolecular complexes containing a pore-forming α subunit and one or more β subunits. The VGSC α subunit gene family consists of 10 members, which have distinct tissue-specific and developmental expression profiles. So far, four β subunits (β1—β4) and one splice variant of β1 (β1A, also called β1B) have been identified. VGSC β subunits are multifunctional, serving as modulators of channel activity, regulators of channel cell surface expression, and as members of the immunoglobulin superfamily, cell adhesion molecules (CAMs). β subunits are substrates of β-amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase, yielding intracellular domains (ICDs) that may further modulate cellular activity via transcription. Recent evidence shows that β1 regulates migration and pathfinding in the developing postnatal CNS in vivo. The α and β subunits, together with other components of the VGSC signaling complex, may have dynamic interactive roles depending on cell/tissue type, developmental stage, and pathophysiology. In addition to excitable cells like nerve and muscle, VGSC α and β subunits are functionally expressed in cells that are traditionally considered nonexcitable, including glia, vascular endothelial cells, and cancer cells. In particular, the α subunits are up-regulated in line with metastatic potential and are proposed to enhance cellular migration and invasion. In contrast to the α subunits, β1 is more highly expressed in weakly metastatic cancer cells, and evidence suggests that its expression enhances cellular adhesion. Thus, novel roles are emerging for VGSC α and β subunits in regulating migration during normal postnatal development of the CNS as well as during cancer metastasis.