Dual roles of voltage-gated sodium channels in development and cancer

Voltage-gated Na+ channels (VGSCs) are heteromeric protein complexes containing pore-forming alpha subunits together with non-pore-forming beta subunits. There are nine alpha subunits, Na(v)1.1-Na(v)1.9, and four beta subunits, beta 1-beta 4. The beta subunits are multifunctional, modulating channel activity, cell surface expression, and are members of the immunoglobulin superfamily of cell adhesion molecules. VGSCs are classically responsible for action potential initiation and conduction in electrically excitable cells, including neurons and muscle cells. In addition, through the beta 1 subunit, VGSCs regulate neurite outgrowth and pathfinding in the developing central nervous system. Reciprocal signalling through Na(v)1.6 and beta 1 collectively regulates Na+ current, electrical excitability and neurite outgrowth in cerebellar granule neurons. Thus, alpha and beta subunits may have diverse interacting roles dependent on cell/tissue type. VGSCs are also expressed in non-excitable cells, including cells derived from a number of types of cancer. In cancer cells, VGSC alpha and beta subunits regulate cellular morphology, migration, invasion and metastasis. VGSC expression associates with poor prognosis in several studies. It is hypothesised that VGSCs are up-regulated in metastatic tumours, favouring an invasive phenotype. Thus, VGSCs may have utility as prognostic markers, and/or as novel therapeutic targets for reducing/preventing metastatic disease burden. VGSCs appear to regulate a number of key cellular processes, both during normal postnatal development of the CNS and during cancer metastasis, by a combination of conducting (i. e. via Na+ current) and non-conducting mechanisms.