Voltage-gated sodium channel Nav1.6 (sodium voltage-gated channel alpha subunit 8) (Nav1.6)

The voltage-gated sodium channel Nav1.6, encoded by the SCN8A gene (sodium voltage-gated channel alpha subunit 8), is a critical regulator of neuronal excitability with widespread expression in the central and peripheral nervous systems. It mediates action potential initiation and propagation through fast activation and inactivation kinetics, while uniquely generating persistent and resurgent sodium currents that influence neuronal firing patterns. Structurally, Nav1.6 consists of a single alpha subunit with four homologous domains (DI-DIV), each featuring six transmembrane segments (S1-S6), where S1-S4 form the voltage-sensing domain and S5-S6 form the pore module; cryo-EM structures reveal an inactivated state with closed pore and "up" voltage-sensing domains. Pathologically, over 250 SCN8A mutations show gain-of-function variants causing severe epileptic encephalopathies and loss-of-function linked to generalized epilepsy, alongside roles in Alzheimer's disease via amyloid-β-induced hyperexcitability and Parkinson's via astrocyte upregulation contributing to motor deficits. In glioblastoma, it promotes proliferation, migration, and inhibits apoptosis through Na+/H+ exchanger-1 and ERK-AKT pathways. Therapeutic interest focuses on Nav1.6-selective blockers like XEN901 and GS967 to mitigate hyperexcitability, with challenges from subtype-specific modulation and post-translational effects like glycosylation and palmitoylation impacting localization and excitability. Auxiliary subunits (e.g., β1, β4) and factors like fibroblast growth factor homologous factors further tune its function.

Other names

SCN8Asodium voltage-gated channel alpha subunit 8

Selective blockade (Nav1.6-selective blockers); Inhibition of sodium influx; Modulation of persistent and resurgent sodium currents