An emerging role for voltage-gated Na+ channels in cellular migration: Regulation of central nervous system development and potentiation of invasive cancers

摘要

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 ten 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 central nervous system (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 to be non-excitable, including glia, vascular endothelial cells, and cancer cells. In particular, the α subunits are upregulated 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.