TRPM8 (transient receptor potential cation channel subfamily M member 8; HGNC:17961, NCBI Gene ID 79054) is a human locus mapped to chromosome band 2q37.1 that encodes TRPM8 cold- and menthol-activated cation channel (1,104 aa). TRPM8 acts in environmental cold thermosensation, tear film regulation & migraine susceptibility, together with TRPV1 Vanilloid Receptor, TRPA1 Irritant Channel Gene, and TRPV4 Channel Gene. Encodes the primary cold- and menthol-activated ion channel of somatosensory neurons.
Approved Symbol
TRPM8
Chromosomal Locus
2q37.1
Encoded Product
TRPM8 cold- and menthol-activated cation channel (1,104 aa)
Primary Pathway
Environmental cold thermosensation, tear film regulation & migraine susceptibility
Clinical / Therapeutic Role
Target of FDA-approved acoltremon for dry eye disease; GWAS locus for migraine
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 25-exon locus on chromosome 2q37.1 encoding a 1,104-amino-acid homotetrameric cation channel lacking N-terminal ankyrin repeats but containing a large melastatin homology region and a C-terminal TRP box that binds phosphatidylinositol 4,5-bisphosphate (PIP2).
Cellular & Tissue Expression Profile: Expressed in a dedicated subpopulation of cold-sensitive C-fiber and A-delta sensory neurons in dorsal root and trigeminal ganglia, corneal afferent nerve endings, and prostate epithelial cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Activated by innocuously cool to noxious cold temperatures (below 26 degrees C) and by chemical cooling mimetics including menthol, icilin, and eucalyptol, conducting inward Na+ and Ca2+ currents that depolarize cold thermoreceptors.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Genome-wide association studies consistently identify common non-coding variants upstream of TRPM8 as one of the strongest genetic susceptibility loci for migraine headache and cold allodynia.
Therapeutic & Clinical Pharmacology: Topical TRPM8 agonists such as acoltremon stimulate corneal trigeminal cold thermoreceptors to restore basal tear secretion in dry eye disease, whereas antagonists are investigated for oxaliplatin-induced cold allodynia and migraine.