TRPM8

Transient receptor potential cation channel, subfamily M, member 8
Identifiers
Symbols	TRPM8; LTRPC6; MGC2849; TRPP8
External IDs	OMIM: 606678 MGI: 2181435 HomoloGene: 23433 IUPHAR: TRPM8 GeneCards: TRPM8 Gene
Gene Ontology Molecular function • ion channel activity • calcium channel activity • protein homodimerization activity Cellular component • external side of plasma membrane • membrane • integral to membrane Biological process • ion transport • cellular calcium ion homeostasis • response to cold • response to stimulus • thermoception • protein homotetramerization • transmembrane transport • protein homotrimerization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	79054	171382
Ensembl	ENSG00000144481	ENSMUSG00000036251
UniProt	Q7Z2W7	Q148W9
RefSeq (mRNA)	NM_024080.4	NM_134252.3
RefSeq (protein)	NP_076985.4	NP_599013.1
Location (UCSC)	Chr 2: 234.83 – 234.93 Mb	Chr 1: 90.17 – 90.29 Mb
PubMed search	[1]	[2]

Transient receptor potential cation channel subfamily M member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene.^[1]

Function

TRPM8 is an ion channel, upon activation it allows the entry of Na⁺ (sodium) and Ca²⁺ (calcium) ions to the cell that leads to depolarization and the generation of an action potential. This eventually leads to the feeling of cold.

The TRPM8 protein is expressed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as menthol and icilin where as WS-12 and CPS-369 are the most selective agonist of TRPM8.^[2][3]

TRPM8 is also expressed in the prostate, lungs, and bladder where its function is not very well understood.

Clinical significance

Cold-patches have traditionally been used to induce analgesia or relief in pain which is caused as result of traumatic injuries. The underlying mechanism of cold-induced analgesia remained obscure until the discovery of TRPM8.

One research group has reported that TRPM8 is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 °C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons of afferent nerve fibers.^[4]

Three independent research groups have reported that mice lacking TRPM8 gene are severely impaired in their ability to detect cold temperatures.^[5] Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli. Many research groups, both in universities and pharmaceutical companies, are now actively involved in looking for selective TRPM8 ligands to be used as new generation of neuropathic analgesic drugs. Interestingly, low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions,^[6] whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers.^[7]

TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain.^[8] Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models.^[9]

TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes.^[10] Furthermore, TRPM8 is upregulated in many prostate cancer cell lines and Dendreon/Genentech are pursuing an agonist approach to induce apoptosis and prostate cancer cell death.^[11]

See also

• TRPM

References

1. ^ Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological reviews 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID 16382100. 
2. ^ Sherkheli M.A. et al. (2007). "Selective TRPM8 agonists: a novel group of neurophathic analgesics". FEBS Journal 274 (s1): 232. doi:10.1111/j.0014-2956.2007.05861_4.x. 
3. ^ Sherkheli M.A., G G, Ak VE, Jf D, H H (October 2008). "Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels". Pak J Pharm Sci 21 (4): 370–8. PMID 18930858. http://www.pjps.pk/. 
4. ^ Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D (2007). "The menthol receptor TRPM8 is the principal detector of environmental cold.". Nature 448 (7150): 204–208. doi:10.1038/nature05910. PMID 17538622. 
5. ^ Daniels RL, McKemy DD (2007). "Mice left out in the cold: commentary on the phenotype of TRPM8-nulls". Mol Pain 3 (1): 23. doi:10.1186/1744-8069-3-23. PMC 1988789. PMID 17705869. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1988789. 
6. ^ Proudfoot CJ, Garry EM, Cottrell DF, Rosie R, Anderson H, Robertson DC, Fleetwood-Walker SM, Mitchell R (August 2006). "Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain". Current biology : CB 16 (16): 1591–605. doi:10.1016/j.cub.2006.07.061. PMID 16920620. 
7. ^ Wasner G, Schattschneider J, Binder A, Baron R (May 2004). "Topical menthol--a human model for cold pain by activation and sensitization of C nociceptors". Brain : a journal of neurology 127 (Pt 5): 1159–71. doi:10.1093/brain/awh134. PMID 14985268. 
8. ^ Colburn RW, Lubin ML, Stone DJ Jr, Wang Y, Lawrence D, D'Andrea MR, Brandt MR, Liu Y, Flores CM, Qin N (May 2007). "Attenuated cold sensitivity in TRPM8 null mice". Neuron 54 (3): 379–86. doi:10.1016/j.neuron.2007.04.017. PMID 17481392. 
9. ^ Lashinger ES, Steiginga MS, Hieble JP, Leon LA, Gardner SD, Nagilla R, Davenport EA, Hoffman BE, Laping NJ, Su X (September 2008). "AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome". American journal of physiology. Renal physiology 295 (3): F803–10. doi:10.1152/ajprenal.90269.2008. PMID 18562636. 
10. ^ Mukerji G, Yiangou Y, Corcoran SL, Selmer IS, Smith GD, Benham CD, Bountra C, Agarwal SK, Anand P (2006). "Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations". BMC urology 6: 6. doi:10.1186/1471-2490-6-6. PMC 1420318. PMID 16519806. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1420318. 
11. ^ "Dendreon: Targeting Cancer, Transforming Lives". Dendreon Corporation. 2005-09-21. http://investor.dendreon.com/ReleaseDetail.cfm?ReleaseID=174120&Header=News. Retrieved 2008-10-31. ^{[dead link]}

Further reading

• Clapham DE, Julius D, Montell C, Schultz G (2006). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels.". Pharmacol. Rev. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID 16382100. 
• Voets T, Owsianik G, Nilius B (2007). "TRPM8.". Handb Exp Pharmacol 179 (179): 329–44. doi:10.1007/978-3-540-34891-7_20. PMID 17217067. 

External links

• MeSH TRPM8+protein,+human

Na+: Sodium channel
Constitutively active Epithelial sodium channel (α, β, γ, δ) Proton gated Amiloride-sensitive cation channel (1, 2, 3, 4) Voltage-gated Navα (1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 7A) · Navβ (1, 2, 3, 4)

K+: Potassium channel
Voltage-gated Kvα1-6 (1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8) · (2.1, 2.2) · (3.1, 3.2, 3.3, 3.4) · (4.1, 4.2, 4.3) · (5.1) · (6.1, 6.2, 6.3, 6.4) Kvα7-12 (7.1, 7.2, 7.3, 7.4, 7.5) · (8.1, 8.2) · (9.1, 9.2, 9.3) · (10.1, 10.2) · (11.1/hERG, 11.2, 11.3) · (12.1, 12.2, 12.3) Kvβ (1, 2, 3) · KCNIP (1, 2, 3, 4) · minK/ISK · minK/ISK-like · MiRP (1, 2, 3) · Shaker gene Calcium-activated BK channel (α1, β1, β2, β3, β4) · SK channel (SK1, SK2, SK3, SK4) · KCa (1.1, 2.1, 2.2, 2.3, 3.1, 4.1, 4.2, 5.1) Inward-rectifier KATP · Kir (1.1, 2.1, 2.2, 2.3, 2.4, 2.6) · GIRK/Kir (3.1, 3.2, 3.3, 3.4) · Kir (4.1, 4.2, 5.1, 6.1, 6.2, 7.1) Tandem pore domain K2P (1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, 16, 17, 18)

Other
Cl-: Chloride channel ANO1 · Bestrophin (1, 2) · CFTR · CLCA (1, 2, 3, 4) · CLCN (1, 2, 3, 4, 5, 6, 7, KA, KB) · CLIC (1, 2, 3, 4, 5, 6, L1) · CLNS (1A, 1B) H+: Voltage-gated HVCN1 M+: TRP cation channel TRPA (1) · TRPC (1, 2, 3, 4, 4AP, 5, 6, 7) · TRPM (1, 2, 3, 4, 5, 6, 7, 8) · TRPML (1, 2, 3) · TRPP (1, 2) · TRPV (1, 2, 3, 4, 5, 6) Cyclic nucleotide-gated (FC) α (1, 2, 3, 4) · β (1, 2, 3) · HCN (1, 2, 3, 4) Porin Aquaporin (1, 2, 3, 4, 5, 7, 8, 9) · Voltage-dependent anion channel (1, 2, 3) · General bacterial porin family Gap junction Connexin: A (GJA1, GJA3, GJA4, GJA5, GJA8, GJA9, GJA10) · B (GJB1, GJB2, GJB3, GJB4, GJB5, GJB6, GJB7) · C (GJC1, GJC2, GJC3) · D (GJD2, GJD3, GJD4)) Innexin General Ligand-gated ion channel · Voltage-gated ion channel · Stretch-activated ion channel

see also disorders
B memb: cead, trns (1A, 1C, 1F, 2A, 3A1, 3A2-3, 3D), othr