Developmental and Regulatory Functions of Na(+) Channel Non-pore-forming β Subunits.

Voltage-gated Na(+) channels (VGSCs) isolated from mammalian neurons are heterotrimeric complexes containing one pore-forming α subunit and two non-pore-forming β subunits. In excitable cells, VGSCs are responsible for the initiation of action potentials. VGSC β subunits are type I topology glycoproteins, containing an extracellular amino-terminal immunoglobulin (Ig) domain with homology to many neural cell adhesion molecules (CAMs), a single transmembrane segment, and an intracellular carboxyl-terminal domain. VGSC β subunits are encoded by a gene family that is distinct from the α subunits. While α subunits are expressed in prokaryotes, β subunit orthologs did not arise until after the emergence of vertebrates. β subunits regulate the cell surface expression, subcellular localization, and gating properties of their associated α subunits. In addition, like many other Ig-CAMs, β subunits are involved in cell migration, neurite outgrowth, and axon pathfinding and may function in these roles in the absence of associated α subunits. In sum, these multifunctional proteins are critical for both channel regulation and central nervous system development.