A new look at sodium channel beta subunits

Voltage-gated sodium (Na-v) 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 Na-v channels are implicated in a wide variety of inherited pathologies, including cardiac conduction diseases, myotonic conditions, epilepsy and chronic pain syndromes. Drugs active against Na-v channels are used as local anaesthetics, anti-arrhythmics, analgesics and anti-convulsants. The Na-v channels are composed of a pore-forming a subunit and associated beta subunits. The beta subunits are members of the immunoglobulin (Ig) domain family of cell-adhesion molecules. They modulate multiple aspects of Na-v channel behaviour and play critical roles in controlling neuronal excitability. The recently published atomic resolution structures of the human beta 3 and beta 4 subunit Ig domains open a new chapter in the study of these molecules. In particular, the discovery that beta 3 subunits form trimers suggests that Na-v channel oligomerization may contribute to the functional properties of some beta subunits.