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Gene Review

TRPM8  -  transient receptor potential cation...

Homo sapiens

Synonyms: LTRPC6, LTrpC-6, LTrpC6, Long transient receptor potential channel 6, TRPP8, ...
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Disease relevance of TRPM8


High impact information on TRPM8


Chemical compound and disease context of TRPM8

  • Our results suggest that the TRPM8 may be an important new ER Ca(2+) release channel, potentially involved in a number of Ca(2+)- and store-dependent processes in prostate cancer epithelial cells, including those that are important for prostate carcinogenesis, such as proliferation and apoptosis [1].

Biological context of TRPM8


Anatomical context of TRPM8

  • Recent cloning of a cold/menthol-sensitive TRPM8 channel (transient receptor potential melastatine family member 8) from rodent sensory neurons has provided the molecular basis for the cold sensation [1].
  • Surprisingly, the human orthologue of rodent TRPM8 also appears to be strongly expressed in the prostate and in the prostate cancer-derived epithelial cell line, LNCaP [1].
  • We demonstrate that these puzzling results arise from TRPM8 localization not in the plasma, but in the endoplasmic reticulum (ER) membrane of LNCaP cells, where it supports cold/menthol/icilin-induced Ca(2+) release from the ER with concomitant activation of plasma membrane (PM) store-operated channels (SOC) [1].
  • Separation of layers in human bladder demonstrated mRNA for TRPM8 only in the urothelium and not in the detrusor [11].
  • Human samples demonstrated TRPM8 mRNA in prostate, testicle, seminiferous tubules, scrotal skin and bladder [11].

Associations of TRPM8 with chemical compounds

  • We also demonstrate that TRPM8 expression and the magnitude of SOC current associated with it are androgen-dependent [1].
  • In this study, we show that despite such expression, LNCaP cells respond to cold/menthol stimulus by membrane current (I(cold/menthol)) that shows inward rectification and high Ca(2+) selectivity, which are dramatically different properties from "classical" TRPM8-mediated I(cold/menthol) [1].
  • Many transient receptor potential (TRP) channels are activated or blocked by various compounds found in plants; two prominent examples include the activation of TRPV1 channels by capsaicin and the activation of TRPM8 channels by menthol [12].
  • We also show that TRPM8 is modulated by ethanol but unlike TRPV1 is insensitive to extracellular acidification [13].
  • Ethanol inhibits cold-menthol receptor TRPM8 by modulating its interaction with membrane phosphatidylinositol 4,5-bisphosphate [14].

Regulatory relationships of TRPM8

  • Double labeling analysis revealed that TRPM8 immunoreactivity was co-expressed with a part of TRPV1 or CGRP-immunoreactive neurons in TG [15].

Other interactions of TRPM8

  • In contrast, 2APB inhibits the activity of TRPC6 and TRPM8 evoked by 1-oleolyl-2-acetyl-sn-glycerol and menthol, respectively [16].
  • TRPV2, TRPM8, and TRPA1 are also very likely to be involved in thermal nociception, because their activation thresholds are within the noxious range of temperatures [17].
  • Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement [8].
  • Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8 [13].
  • TRPM5, which is distantly related to TRPM8, is a Ca2+-activated cation channel expressed in taste cells that is essential for sweet, bitter, and umami tastes [18].

Analytical, diagnostic and therapeutic context of TRPM8

  • Immunofluorescence staining for TRPM8 was performed in rat tissues as well as in cultured human urothelial cells [11].
  • Whole-cell recordings show that TRPM8 is permeable to multiple cations and exhibits a strong outward rectification [19].
  • Several members of the transient receptor potential (TRP) family of ion channels have been implicated as transducers of thermal stimuli, including TRPV1 and TRPV2, which are activated by heat, and TRPM8, which is activated by cold [20].
  • RT-PCR was used to show the presence of six temperature-sensitive TRP channel transcripts (TRPV1-4, TRPN1, and TRPM8) in whole nodose ganglia [21].
  • Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain [22].


  1. Novel role of cold/menthol-sensitive transient receptor potential melastatine family member 8 (TRPM8) in the activation of store-operated channels in LNCaP human prostate cancer epithelial cells. Thebault, S., Lemonnier, L., Bidaux, G., Flourakis, M., Bavencoffe, A., Gordienko, D., Roudbaraki, M., Delcourt, P., Panchin, Y., Shuba, Y., Skryma, R., Prevarskaya, N. J. Biol. Chem. (2005) [Pubmed]
  2. TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Namer, B., Seifert, F., Handwerker, H.O., Maihöfner, C. Neuroreport (2005) [Pubmed]
  3. Noxious cold stimulation induces mitogen-activated protein kinase activation in transient receptor potential (TRP) channels TRPA1- and TRPM8-containing small sensory neurons. Mizushima, T., Obata, K., Katsura, H., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Tokunaga, A., Mashimo, T., Noguchi, K. Neuroscience (2006) [Pubmed]
  4. A TRP channel that senses cold stimuli and menthol. Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A., Story, G.M., Earley, T.J., Dragoni, I., McIntyre, P., Bevan, S., Patapoutian, A. Cell (2002) [Pubmed]
  5. High-throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol. Bandell, M., Dubin, A.E., Petrus, M.J., Orth, A., Mathur, J., Hwang, S.W., Patapoutian, A. Nat. Neurosci. (2006) [Pubmed]
  6. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Bandell, M., Story, G.M., Hwang, S.W., Viswanath, V., Eid, S.R., Petrus, M.J., Earley, T.J., Patapoutian, A. Neuron (2004) [Pubmed]
  7. Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells. Zhang, L., Barritt, G.J. Cancer Res. (2004) [Pubmed]
  8. Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement. Bidaux, G., Roudbaraki, M., Merle, C., Crépin, A., Delcourt, P., Slomianny, C., Thebault, S., Bonnal, J.L., Benahmed, M., Cabon, F., Mauroy, B., Prevarskaya, N. Endocr. Relat. Cancer (2005) [Pubmed]
  9. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V., Nilius, B. Nature (2004) [Pubmed]
  10. Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl)anthranilic acid. Kraft, R., Grimm, C., Frenzel, H., Harteneck, C. Br. J. Pharmacol. (2006) [Pubmed]
  11. Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. Stein, R.J., Santos, S., Nagatomi, J., Hayashi, Y., Minnery, B.S., Xavier, M., Patel, A.S., Nelson, J.B., Futrell, W.J., Yoshimura, N., Chancellor, M.B., De Miguel, F. J. Urol. (2004) [Pubmed]
  12. Bisandrographolide from Andrographis paniculata Activates TRPV4 Channels. Smith, P.L., Maloney, K.N., Pothen, R.G., Clardy, J., Clapham, D.E. J. Biol. Chem. (2006) [Pubmed]
  13. Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8. Weil, A., Moore, S.E., Waite, N.J., Randall, A., Gunthorpe, M.J. Mol. Pharmacol. (2005) [Pubmed]
  14. Ethanol inhibits cold-menthol receptor TRPM8 by modulating its interaction with membrane phosphatidylinositol 4,5-bisphosphate. Benedikt, J., Teisinger, J., Vyklicky, L., Vlachova, V. J. Neurochem. (2007) [Pubmed]
  15. TRPM8 protein localization in trigeminal ganglion and taste papillae. Abe, J., Hosokawa, H., Okazawa, M., Kandachi, M., Sawada, Y., Yamanaka, K., Matsumura, K., Kobayashi, S. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  16. 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. Hu, H.Z., Gu, Q., Wang, C., Colton, C.K., Tang, J., Kinoshita-Kawada, M., Lee, L.Y., Wood, J.D., Zhu, M.X. J. Biol. Chem. (2004) [Pubmed]
  17. Thermosensation and pain. Tominaga, M., Caterina, M.J. J. Neurobiol. (2004) [Pubmed]
  18. Thermal gating of TRP ion channels: food for thought? Liman, E.R. Sci. STKE (2006) [Pubmed]
  19. Biophysical properties of menthol-activated cold receptor TRPM8 channels. Hui, K., Guo, Y., Feng, Z.P. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  20. Heat-evoked activation of the ion channel, TRPV4. Güler, A.D., Lee, H., Iida, T., Shimizu, I., Tominaga, M., Caterina, M. J. Neurosci. (2002) [Pubmed]
  21. Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse. Zhang, L., Jones, S., Brody, K., Costa, M., Brookes, S.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  22. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Proudfoot, C.J., Garry, E.M., Cottrell, D.F., Rosie, R., Anderson, H., Robertson, D.C., Fleetwood-Walker, S.M., Mitchell, R. Curr. Biol. (2006) [Pubmed]
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