Thursday, August 23, 2012

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 (Nav1.1– Nav1.9), each with a unique central and peripheral nervous system distribution had been identified. 4 closely related sodium channels (Nav 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 Nav1.1, -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.

Nav1.7 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 Nav1.7 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 Nav1.7 are pain sensing (nociceptive), suggesting a role for this sodium channel in the pathogenesis of pain. In addition to Nav1.7, Nav1.8 and Nav1.9 are also predominantly present in small nociceptive sensory neurons and the nerve fibres emanating from them.

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