Na+ channel beta subunits: overachievers of the ion channel family

Voltage-gated Na+ channels (VGSCs) in mammals contain a pore-forming a subunit and one or more alpha subunits. There are five mammalian beta subunits in total: beta 1, beta 1B, beta 2, beta 3, and beta 4, encoded by four genes: SCN1B-SCN4B. With the exception of the SCN1B splice variant, beta 1B, the beta subunits are type I topology transmembrane proteins. In contrast, beta 1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC beta subunits are multifunctional. While they do not form the ion channel pore, beta subunits alter gating, voltage-dependence, and kinetics of VGSC alpha subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, beta subunits are members of the immunoglobulin superfamily of cell adhesion molecules and regulate cell adhesion and migration. beta subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of beta subunits is beta 1, encoded by SCN1B, that plays a critical role in neuronal migration and pathfinding during brain development, and whose function is dependent on Na+ current and gamma-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. beta subunits are emerging as key players in a wide variety of physiopathologies, including epilepsy, cardiac arrhythmia, multiple sclerosis, Huntington's disease, neuropsychiatric disorders, neuropathic and inflammatory pain, and cancer. beta subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some beta subunit functions may operate independently of alpha subunits. Thus, beta subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.