SCN8A encodes the sodium channel protein type 8 subunit alpha (SCN8A or Nav1.6). As a member of the voltage-gated sodium (Nav) channel family, SCN8A has the typical structure containing four homologous domains (DI-DIV), each with six highly conserved transmembrane segments designated S1-S6. Less-conserved cytoplasmic loops separate domains DI and DII, domains DII and DIII. Domains III and IV are separated by a short, highly conserved inactivation gate. Voltage sensitivity is provided by positively charged arginine and histidine residues in the fourth transmembrane segments (S4). The channel “fast-inactivates” through a hinged lid mechanism (internal DIII-DIV linker) that occludes the intracellular mouth of the pore (composed of the S5-S6 segments of all four domains). SCN8A is predominantly expressed in neurons, and is one of the most abundant sodium channels in the central nervous system (CNS).
|Basic Information of SCN8A|
|Protein Name||Sodium channel protein type 8 subunit alpha|
|Aliases||Sodium channel protein type VIII subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.6|
|Organism||Homo sapiens (Human)|
SCN8A is abundantly expressed throughout the CNS, with high expression in the cerebellum, hippocampus, cortex and olfactory bulb. Primary motor neurons, as well as cerebellar Purkinje and granule cells, have strong expression of SCN8A, suggesting a role in motor control. SCN8A channels are enriched at the neuronal axon initial segment and nodes of Ranvier, where they promote neuronal excitability by participating in the initiation and propagation of action potentials. SCN8A channels generate persistent current, hyperpolarized thresholds of activation compared with other NaV channels, and resurgent current. These biophysical properties make SCN8A a critical mediator of neuronal excitability. SCN8A mutations have been associated with epilepsy and neurodevelopmental disorders.
Fig.1 Positions of missense mutations of SCN8A in epileptic encephalopathy. (Wagnon, 2015)
This article finds that SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases.
This article suggests that SCN8A as an important candidate gene should be detected in patients with epilepsy of unknown etiology and IDDs. An interesting finding is that SCB might provide satisfied efficacy for epileptic seizure in patients with an SCN8A mutation.
This article suggests that selective targeting of Scn8a activity might be efficacious in patients with epilepsy.
This article reveals that functional differences among pathogenic mutations of SCN8A will have implications for the selection of treatment for individual patients and for the development of new therapies.
This article suggests that complex alterations in the SCN8A gene may underlie epilepsy and cognitive impairment.
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