Sodium channels

Sodium channels

Voltage-gated sodium channels play a critical role in the generation and conduction of action potentials — so important for electrical signalling by most excitable cells. Sodium channels are integral membrane proteins and are comprised of a large α subunit, which forms the voltage-sensitive and ion-selective pore, and smaller auxiliary β subunit(s) that can modulate the kinetics and voltage dependence of channel gating. Till 2007, 9 isoforms of the sodium-channel α subunit (Na_v1.1– Na_v1.9), each with a unique central and peripheral nervous system distribution had been identified. 4 closely related sodium channels (Na_v 1.1, -1.2, -1.3, and -1.7) are encoded by a set of 4 genes (SCN1A, SCN2A, SCN3A, and SCN9A, respectively) located within a cluster on chromosome 2q24.3. Mutations in the genes encoding Na_v1.1, -1.2, and -1.3 are responsible for a group of epilepsy syndromes with overlapping clinical characteristics but divergent clinical severity, mutation in the gene encoding Nav1.7 has a critical role in pain sensation.

Na_v1.7 is encoded by SCN9A, a 113.5-kb gene comprising 26 exons (OMIM 603415). he encoded sodium channel is composed of 1977 amino acids organized into 4 domains, each with 6 transmembrane segments, and is predominantly expressed in the dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons.

Immunohistochemical studies show that Na_v1.7 is present at the distal ends of the wire-like projections of neurons known as neuritis, close to the impulse trigger zone where neuronal firing is initiated.

Interestingly, the large majority of DRG neurons that express Na_v1.7 are pain sensing (nociceptive), suggesting a role for this sodium channel in the pathogenesis of pain. In addition to Na_v1.7, Na_v1.8 and Na_v1.9 are also predominantly present in small nociceptive sensory neurons and the nerve fibres emanating from them.