The role of non-pore-forming β subunits in physiology and pathophysiology of voltage-gated sodium channels.

Voltage-gated sodium channel β1 and β2 subunits were discovered as auxiliary proteins that co-purify with pore-forming α subunits in brain. The other family members, β1B, β3, and β4, were identified by homology and shown to modulate sodium current in heterologous systems. Work over the past 2 decades, however, has provided strong evidence that these proteins are not simply ancillary ion channel subunits, but are multifunctional signaling proteins in their own right, playing both conducting (channel modulatory) and nonconducting roles in cell signaling. Here, we discuss evidence that sodium channel β subunits not only regulate sodium channel function and localization but also modulate voltage-gated potassium channels. In their nonconducting roles, VGSC β subunits function as immunoglobulin superfamily cell adhesion molecules that modulate brain development by influencing cell proliferation and migration, axon outgrowth, axonal fasciculation, and neuronal pathfinding. Mutations in genes encoding β subunits are linked to paroxysmal diseases including epilepsy, cardiac arrhythmia, and sudden infant death syndrome. Finally, β subunits may be targets for the future development of novel therapeutics.