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Sodium Channel B Subunits: Anything but Auxiliary

Department of Pharmocology, The University of Michigan, Ann Arbor

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 subunit and two auxiliary ß subunits. The subunits form a gene family with at least 10 members. Mutations in 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 ß subunits with at least one alternative splice product. A mutation in the ß1 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 ß 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 ß1 subunit. A sodium channel signaling complex is proposed that involves ß subunits as channel modulators as well as cell adhesion molecules, other cell adhesion molecules such as neurofascin and contactin, RPTPß, and extracellular matrix molecules such as tenascin.

Key Words: cell adhesion • voltage-gated ion channel • node of Ranvier • cytoskeleton

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