**3. Mutations in sodium channel subunit genes**

#### **3.1 Voltage-gated sodium channels**

Voltage-gated sodium channels play an essential role in the initiation and propagation of action potentials. These channels open as the membrane depolarizes and inactivate within a few milliseconds of opening. As the membrane polarizes again, the inactivation is removed and a second depolarizing stimulus is able to reopen the channel.

Sodium channels are large, multimeric complexes composed of an α subunit and one or more auxiliary β subunits. The α subunit has four homologous domains, each consisting of six transmembrane helices. The β subunit has one transmembrane segment and an extracellular domain with an immunoglobulin-like fold and belongs to the Ig superfamily of cell adhesion molecules (CAMs) (Catterall, 2000). The association with β subunits modulate cell surface expression and localization, voltage-dependence and kinetics of activation and inactivation, as well as cell adhesion and association with signalling and cytoskeletal molecules (Patino and Isom, 2010). Nine α subunits (NaV1.1 – NaV1.9 encoded by SCN1A-SCN11A) and four β subunits (encoded by SCN1B-SCN4B) have been characterized so far. In addition, the enigmatic NaX channel, which appears not to be gated by voltage but rather by sodium, is encoded by the SCN7A gene (previously assigned as SCN6A) (Hiyama et al., 2002). NaV1.1, NaV1.2, NaV1.3 and NaV1.6 are the sodium channel α subunits most abundantly expressed in the brain (Yu and Catterall, 2003).
