SCN10A (sodium voltage-gated channel alpha subunit 10; HGNC:10582, NCBI Gene ID 6336) is a human locus mapped to chromosome band 3p22.2 that encodes voltage-gated sodium channel alpha subunit Nav1.8 (1,956 aa). SCN10A acts in nociceptive action potential electrogenesis & cold pain transmission, together with SCN9A (Nav1.7 Channel Gene), SCN11A (Nav1.9 Channel Gene), and SCN5A (Nav1.5 Cardiac Channel Gene). Encodes the tetrodotoxin-resistant Nav1.8 sodium channel driving repetitive firing in nociceptors.
Target of selective Nav1.8 inhibitor suzetrigine (VX-548) for acute & neuropathic pain
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 27-exon gene located at 3p22.2 adjacent to SCN5A and SCN11A, encoding a 1,956-residue pore-forming alpha subunit in which a serine substitution in the domain I pore loop confers resistance to nanomolar tetrodotoxin (TTX-R).
Cellular & Tissue Expression Profile: Restricted almost exclusively to small- and medium-diameter peripheral C-fiber and A-delta nociceptors in dorsal root, trigeminal, and nodose ganglia, with minimal expression in central nervous system neurons.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Exhibits depolarized voltage dependence of activation and rapid recovery from inactivation, carrying the majority of the inward sodium current during the action potential upstroke in depolarized nociceptive terminals and maintaining repetitive firing even at noxious cold temperatures where TTX-sensitive channels inactivate.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Gain-of-function missense variants in SCN10A cause painful small-fiber neuropathy with hyperexcitable C-fibers, while non-coding polymorphisms in SCN10A enhancers modulate cardiac PR and QRS conduction intervals through enhancer sharing with neighboring SCN5A.
Therapeutic & Clinical Pharmacology: Validated non-opioid analgesic target of suzetrigine (VX-548), an oral state-dependent selective Nav1.8 inhibitor that suppresses peripheral pain transmission without central nervous system sedation or addiction liability.