A new look at sodium channel β subunits

Abstract

Voltage-gated sodium (Nav) channels are intrinsic plasma membrane proteins that initiate the action potential in electrically excitable cells. They are a major focus of research in neurobiology, structural biology, membrane biology and pharmacology. Mutations in Nav channels are implicated in a wide variety of inherited pathologies, including cardiac conduction diseases, myotonic conditions, epilepsy and chronic pain syndromes. Drugs active against Nav channels are used as local anaesthetics, anti-arrhythmics, analgesics and anti-convulsants. The Nav channels are composed of a pore-forming α subunit and associated β subunits. The β subunits are members of the immunoglobulin (Ig) domain family of cell-adhesion molecules. They modulate multiple aspects of Nav channel behaviour and play critical roles in controlling neuronal excitability. The recently published atomic resolution structures of the human β3 and β4 subunit Ig domains open a new chapter in the study of these molecules. In particular, the discovery that β3 subunits form trimers suggests that Nav channel oligomerization may contribute to the functional properties of some β subunits.

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…Accessory subunits (b1-4, SCN1B-SCN4B) can associate with the a-subunit and influence channel expression, trafficking, and gating. [48][49][50] All b-subunits and Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 are expressed in the brain. 51 Mutations in both a-or b-subunits have been associated, among other disorders, with epilepsy.…”

The multi-faceted aspects of the complex cardiac Nav1.5 protein in membrane function and pathophysiology

“…These 4 domains assemble in a specific 3D-structure to create an aqueous pore, with alternation of positive charges, which connects the cytoplasmic compartment of the cell to the extracellular medium ( Fig. 1B) [4]. This 3D organization exposes specific binding sites and facilitates ion movement.…”

“…This family consists of 9 members (Na v 1.1-1.9), encoded by 9 genes (SCN1-5A, and SCN8-11A); the amino acid sequences of the proteins are more than 50% homologous [4]. These channels consist of the heteromeric assembly of an α-subunit (the pore-forming component) which is functionally modulated by its association with two ancillary β-subunits.…”

“…ACCEPTED MANUSCRIPT 5 subunit, and they probably serve to facilitate sodium channel migration towards the cell membrane by directly interacting with the α-subunit [4].…”

“…The S4 segment (voltage sensor) of each domain contains positively charged amino acids that alternate every 3 or 4 positions. The movement of S4, following voltage variation (depolarization), causes channel opening [4].…”