TRPA1 (transient receptor potential cation channel subfamily A member 1; HGNC:497, NCBI Gene ID 8989) is a human locus mapped to chromosome band 8q21.11 that encodes TRPA1 reactive-electrophile & nociceptive cation channel (1,119 aa). TRPA1 acts in chemonociception, neurogenic inflammation & oxidative stress sensing, together with TRPV1 Vanilloid Receptor, TRPV4 Channel Gene, and TRPM8 Cold Receptor Gene. Encodes the electrophile-sensing TRPA1 cation channel detecting pungent irritants and endogenous oxidative stress.
Familial episodic pain syndrome type 1 (FEPS1); target for cough & inflammatory pain
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 27-exon gene at 8q21.11 encoding a 1,119-residue subunit distinguished by an elongated cytoplasmic N-terminus containing 14 to 17 ankyrin repeat domains and reactive cysteine/lysine nucleophiles (Cys621, Cys641, Cys665).
Cellular & Tissue Expression Profile: Co-expressed with TRPV1 in peptidergic C-fiber and A-delta nociceptors of dorsal root, trigeminal, and vagal jugular/nodose ganglia innervating skin,viscera, and respiratory airways.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Opens upon covalent modification of reactive N-terminal cysteines by exogenous electrophiles (allyl isothiocyanate in mustard oil and wasabi, cinnamaldehyde, acrolein in smoke) and endogenous lipid peroxidation products (4-hydroxynonenal, prostaglandins), triggering Ca2+ influx and release of substance P (TAC1) and CGRP.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Heterozygous gain-of-function point mutation p.Asn855Ser in the S4 transmembrane helix causes autosomal dominant familial episodic pain syndrome type 1 (FEPS1), characterized by debilitating upper-body pain episodes triggered by fasting, cold, and physical fatigue.
Therapeutic & Clinical Pharmacology: Selective TRPA1 antagonists are under clinical development for chronic neurogenic cough, allergic asthma, diabetic peripheral neuropathy, and inflammatory pruritus.