Na+ Channel ß Subunits : Overachievers of the Ion Channel Family

Voltage-gated Na(+) channels (VGSCs) in mammals contain a pore-forming a subunit and one or more ß subunits. There are five mammalian ß subunits in total: ß1, ß1B, ß2, ß3, and ß4, encoded by four genes: SCN1B-SCN4B. With the exception of the SCN1B splice variant, ß1B, the ß subunits are type I topology transmembrane proteins. In contrast, ß1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC ß subunits are multifunctional. While they do not form the ion channel pore, ß subunits alter gating, voltage-dependence, and kinetics of VGSCa subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, ß subunits are members of the immunoglobulin superfamily of cell adhesion molecules and regulate cell adhesion and migration. ß subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of ß subunits is ß1, 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 ¿-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. ß 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. ß subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some ß subunit functions may operate independently of a subunits. Thus, ß subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.