Sodium Channel β Subunits: Anything but Auxiliary

Abstract

Voltage-gated sodium channels are glycoprotein complexes responsible for initiation and propagation of action potentials in excitable cells such as central and peripheral neurons, cardiac and skeletal muscle myocytes, and neuroendocrine cells. Mammalian sodium channels are heterotrimers, composed of a central, pore-forming alpha subunit and two auxiliary beta subunits. The alpha subunits form a gene family with at least 10 members. Mutations in alpha subunit genes have been linked to paroxysmal disorders such as epilepsy, long QT syndrome, and hyperkalemic periodic paralysis in humans, and motor endplate disease and cerebellar ataxia in mice. Three genes encode sodium channel beta subunits with at least one alternative splice product. A mutation in the beta 1 subunit gene has been linked to generalized epilepsy with febrile seizures plus type 1 (GEFS + 1) in a human family with this disease. Sodium channel beta subunits are multifunctional. They modulate channel gating and regulate the level of channel expression at the plasma membrane. More recently, they have been shown to function as cell adhesion molecules in terms of interaction with extracellular matrix, regulation of cell migration, cellular aggregation, and interaction with the cytoskeleton. Structure-function studies have resulted in the preliminary assignment of functional domains in the beta 1 subunit. A sodium channel signaling complex is proposed that involves beta subunits as channel modulators as well as cell adhesion molecules, other cell adhesion molecules such as neurofascin and contactin, RPTP beta, and extracellular matrix molecules such as tenascin.

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

“…The GEFSϩ M1841T mutation of Na v 1.1 ␣ subunit (Annesi et al, 2003) that we studied is depicted as a black circle. ␤ subunits are related proteins with a large extracellular Ig-like domain, a single transmembrane segment and a short cytoplasmic C-terminal region; the Ig-like domain is stabilized by an intramolecular disulfide bridge (Catterall, 2000;Isom, 2001). Lymphocyte T-killer CD8 receptor, which we used as negative control, has a similar structure (Cole and Gao, 2004).…”

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…Sodium channels are heterotrimers, composed of a single, pore-forming α subunit and two β subunits [3]: a noncovalently linked subunit (β1 or β3) [4,5] and a disulfide-linked subunit (β2 or β4) [6,7]. β subunits are multi-functional molecules that regulate channel cell-surface expression levels and modulate channel function, affecting channel kinetics and voltage-dependence in vitro [8]. β subunits also function in vitro as homophilic and/or heterophilic cell adhesion molecules that recruit cytoskeletal ankyrin following homophilic cell adhesion [9][10][11].…”

Cardiac ion channels

“…The accessory b subunits (b1¡b4) are not required to form functional channels but may affect trafficking and/or biophysical characteristics of the channel. 1 The main sodium channel subtypes found in the heart are the tetrodotoxin (TTX) insensitive subtypes Nav1.5 and Nav1.8. Expression of TTX-sensitive sodium channels has been described, 2 but the lack of cardiovascular effects of TTX in animals and human victims of accidental TTX poisoning suggests that these channels contribute little to normal cardiac function.…”