View source for Biology:TRPM8

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Transient receptor potential cation channel subfamily M (melastatin) member 8''' (TRPM8), also known as the '''cold and menthol receptor 1''' (CMR1), is a [[Biology:Protein|protein]] that in humans is encoded by the ''TRPM8'' [[Biology:Gene|gene]].<ref name="pmid23963768">{{cite journal | vauthors = Andersen HH, Olsen RV, Møller HG, Eskelund PW, Gazerani P, Arendt-Nielsen L | title = A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia | journal = European Journal of Pain | volume = 18 | issue = 3 | pages = 315–25 | date = March 2014 | pmid = 23963768 | doi = 10.1002/j.1532-2149.2013.00380.x | s2cid = 35385748 | doi-access = free }}</ref><ref name="pmid16382100">{{cite journal | vauthors = Clapham DE, Julius D, Montell C, Schultz G | title = International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 427–50 | date = December 2005 | pmid = 16382100 | doi = 10.1124/pr.57.4.6 | s2cid = 17936350 }}</ref> The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans.<ref name="pmid23963768"/><ref name="pmid 24664788"/> In addition, mints can desensitize a region through the activation of TRPM8 receptors (the 'cold'/menthol receptor).<ref name="pmid16945367">{{cite journal | vauthors = Werkheiser JL, Rawls SM, Cowan A | title = Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats | journal = European Journal of Pharmacology | volume = 547 | issue = 1–3 | pages = 101–5 | date = October 2006 | pmid = 16945367 | doi = 10.1016/j.ejphar.2006.07.026 }}</ref>

== Structure ==
The TRPM8 channel is a [[Biology:Homotetramer|homotetramer]], composed of four identical subunits with a [[Biology:Transmembrane domain|transmembrane domain]] with six helices (S1–6). The first four, S1–4, act as the voltage sensor and allow binding of [[Chemistry:Menthol|menthol]], [[Chemistry:Icilin|icilin]] and similar channel agonists. S5 and S6 and a connecting loop, also part of the structure, make up the pore, a non-selective cation channel which consists of a highly conserved [[Chemistry:Hydrophobic|hydrophobic]] region. A range of diverse components are required for the high level of specificity in response to cold and menthol stimuli which eventually lead to ion flow through the protein channel.<ref name="pmid19230823">{{cite journal | vauthors = Pedretti A, Marconi C, Bettinelli I, Vistoli G | title = Comparative modeling of the quaternary structure for the human TRPM8 channel and analysis of its binding features | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1788 | issue = 5 | pages = 973–82 | date = May 2009 | pmid = 19230823 | doi = 10.1016/j.bbamem.2009.02.007 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Diver MM, Cheng Y, Julius D | title = Structural insights into TRPM8 inhibition and desensitization | journal = Science | volume = 365 | issue = 6460 | pages = 1434–1440 | date = September 2019 | pmid = 31488702 | pmc = 7262954 | doi = 10.1126/science.aax6672 | bibcode = 2019Sci...365.1434D }}</ref>

== Function ==
TRPM8 is an [[Biology:Ion channel|ion channel]]: upon activation, it allows the entry of [[Chemistry:Sodium|Na]]<sup>+</sup> and [[Chemistry:Calcium|Ca]]<sup>2+</sup> ions into the cell, which leads to depolarization and the generation of an action potential. The signal is conducted from primary afferents (type C- and A-delta) eventually leading to the sensation of cold and cold pain.<ref name="pmid23963768"/>

The TRPM8 protein is expressed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as [[Chemistry:Menthol|menthol]] and [[Chemistry:Icilin|icilin]] whereas WS-12 and CPS-369 are the most selective agonists of TRPM8.<ref>{{cite journal |author=Sherkheli M.A.|title=Selective TRPM8 agonists: a novel group of neurophathic analgesics |journal=FEBS Journal |volume=274 |issue=s1 |page=232 |year=2007 |doi=10.1111/j.0014-2956.2007.05861_4.x |display-authors=0|pmc=7163963 }}</ref><ref name="pmid18930858">{{cite journal | vauthors = Sherkheli MA, Gisselmann G, Vogt-Eisele AK, Doerner JF, Hatt H | title = Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels | journal = Pakistan Journal of Pharmaceutical Sciences | volume = 21 | issue = 4 | pages = 370–8 | date = October 2008 | pmid = 18930858 | url = http://www.pjps.pk/ }}</ref>

TRPM8 is also expressed in the [[Biology:Prostate|prostate]], lungs, and bladder where its function is not well understood.

=== Role in the nervous system ===
The [[Biology:Transient receptor potential channel|transient receptor potential channel]] (TRP) superfamily, which includes the menthol (TRPM8) and [[Chemistry:Capsaicin|capsaicin]] receptors ([[Biology:TRPV1|TRPV1]]), serve a variety of functions in the [[Biology:Peripheral nervous system|peripheral]] and [[Biology:Central nervous system|central nervous system]]s. In the peripheral nervous system, TRPs respond to stimuli from [[Physics:Temperature|temperature]], [[Physics:Pressure|pressure]], [[Medicine:Inflammation|inflammatory agents]], and [[Biology:Receptor (biochemistry)|receptor]] activation. Central nervous system roles of the receptors include neurite outgrowth, receptor signaling, and excitotoxic cell death resulting from noxious stimuli.<ref name="pmid15194117">{{cite journal | vauthors = Moran MM, Xu H, Clapham DE | title = TRP ion channels in the nervous system | journal = Current Opinion in Neurobiology | volume = 14 | issue = 3 | pages = 362–9 | date = June 2004 | pmid = 15194117 | doi = 10.1016/j.conb.2004.05.003 | s2cid = 2410787 }}</ref>

McKemy ''et al.'', 2002 provided some of the first evidence for existence of a cold-activated receptor throughout the mammalian somatosensory system.<ref name="pmid23963768"/> Using [[Biology:Calcium imaging|calcium imaging]] and [[Biology:Patch clamp|patch clamp]] based approaches, they showed a response in dorsal root ganglion (DRG) neurons that exposure to cold, 20&nbsp;°C or cooler, lead to a response in calcium influx. This receptor was shown to respond to both cold temperatures, menthol, and similar now-known agonists of the TRPM8 receptor. It works in conjunction with the [[Biology:TRPV1|TRPV1]] receptor to maintain a feasible threshold temperature range in which our cells are comfortable and our perception of these stimuli occurs at the spinal cord and brain, which integrate signals from different fibers of varying sensitivity to temperature. Application of menthol to skin or mucus membranes results directly in membrane [[Biology:Depolarization|depolarization]], followed by calcium influx via voltage-dependent calcium channels, providing evidence for the role of TRPM8 and other TRP receptors to mediate our sensory interaction with the environment in response to cold in the same way as in response to menthol.<ref name="pmid11882888">{{cite journal | vauthors = McKemy DD, Neuhausser WM, Julius D | title = Identification of a cold receptor reveals a general role for TRP channels in thermosensation | journal = Nature | volume = 416 | issue = 6876 | pages = 52–8 | date = March 2002 | pmid = 11882888 | doi = 10.1038/nature719 | s2cid = 4340358 | bibcode = 2002Natur.416...52M }}</ref>

== Properties ==

=== pH-sensitivity ===
In contrast to the [[Biology:TRPV1|TRPV1]] ([[Chemistry:Capsaicin|capsaicin]]) receptor, which is potentiated by low pH, [[Chemistry:Acid|acid]]ic conditions were shown to inhibit the TRPM8 [[Chemistry:Calcium|Ca<sup>2+</sup>]] response to [[Chemistry:Menthol|menthol]] and [[Chemistry:Icilin|icilin]] (an [[Biology:Agonist|agonist]] of the menthol receptor). It is hypothesized the [[Biology:TRPV1|TRPV1]] and TRPM8 receptors act together in response to inflammatory conditions: [[Biology:TRPV1|TRPV1]], by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain.<ref name="pmid14757700">{{cite journal | vauthors = Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R | title = Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay | journal = British Journal of Pharmacology | volume = 141 | issue = 4 | pages = 737–45 | date = February 2004 | pmid = 14757700 | pmc = 1574235 | doi = 10.1038/sj.bjp.0705652 }}</ref>

=== Sensitization ===
Numerous studies have been published investigating the effect of L-menthol application as a model for TRPM8-sensitization.<ref name="pmid23963768"/><ref name="Patel_2014">{{cite journal | vauthors = Patel R, Gonçalves L, Leveridge M, Mack SR, Hendrick A, Brice NL, Dickenson AH | title = Anti-hyperalgesic effects of a novel TRPM8 agonist in neuropathic rats: a comparison with topical menthol | journal = Pain | volume = 155 | issue = 10 | pages = 2097–107 | date = October 2014 | pmid = 25083927 | pmc = 4220012 | doi = 10.1016/j.pain.2014.07.022 }}</ref> The primary [[Philosophy:Scientific consensus|consensus]] finding is that TRPM8 sensitization increases the sensation of cold pain, also known as cold hyperalgesia.<ref name="pmid23963768"/> An experiment was done in a double-blind two-way crossover study by applying 40% L-menthol to the forearm, using ethanol as a control. Activation of the TRPM8-receptor channel (the primary menthol receptor channel) resulted in increased sensitization to the menthol stimulus. To investigate the mechanisms of this sensitization, Wasner ''et al.'', 2004, performed [[Medicine:Efferent nerve fiber|A fiber]] conduction blockade of the superficial radial nerve in another group of subjects. This ended up reducing the menthol-induced sensation of cold and hyperalgesia because blocking A fiber conduction resulted in inhibition of a class of [[Biology:Group C nerve fiber|group C nerve fiber]] [[Biology:Nociceptor|nociceptor]]s needed to transduce the sensation of pain. They concluded menthol sensitizes cold-sensitive peripheral C nociceptors and activates cold-specific A delta fibers.<ref name="pmid23963768"/><ref name="pmid 24664788">{{cite journal | vauthors = Olsen RV, Andersen HH, Møller HG, Eskelund PW, Arendt-Nielsen L | title = Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers | journal = European Journal of Pain | volume = 18 | issue = 9 | pages = 1333–42 | date = October 2014 | pmid = 24664788 | doi = 10.1002/j.1532-2149.2014.494.x | s2cid = 34286049 }}</ref><ref name="pmid14985268">{{cite journal | vauthors = Wasner G, Schattschneider J, Binder A, Baron R | title = Topical menthol--a human model for cold pain by activation and sensitization of C nociceptors | journal = Brain | volume = 127 | issue = Pt 5 | pages = 1159–71 | date = May 2004 | pmid = 14985268 | doi = 10.1093/brain/awh134 | doi-access = free }}</ref>

=== Desensitization ===
As is common in response to many other sensory stimuli, much experimental evidence exists for the desensitization of human response of TRPM8 receptors to menthol.<ref name="pmid23963768"/> Testing involving administration of menthol and [[Chemistry:Nicotine|nicotine]]-containing cigarettes non-smokers, which induced what they classified as an irritant response, after initial sensitization, showed a declining response in subjects over time, lending itself to the incidence of desensitization. [[Chemistry:Ethanol|Ethanol]], with similar irritant and desensitization properties, was used as a control for nicotine, to distinguish it from menthol-induced response. The menthol receptor was seen to sensitize or desensitize based on cellular conditions, and menthol produces increased activity in Ca<sup>2+</sup>-voltage gated channels that is not seen in ethanol, [[Chemistry:Cyclohexanol|cyclohexanol]] and other irritant controls, suggestive of a specific molecular receptor. Dessirier ''et al.'', 2001, also claim the cross-desensitization of menthol receptors can occur by unknown molecular mechanisms, though they hypothesize the importance of Ca2+ in reducing cell excitability in a way similar to that in the [[Chemistry:Capsaicin|capsaicin]] receptor.<ref name="pmid11399291">{{cite journal | vauthors = Dessirier JM, O'Mahony M, Carstens E | title = Oral irritant properties of menthol: sensitizing and desensitizing effects of repeated application and cross-desensitization to nicotine | journal = Physiology & Behavior | volume = 73 | issue = 1–2 | pages = 25–36 | date = May 2001 | pmid = 11399291 | doi = 10.1016/S0031-9384(01)00431-0 | s2cid = 11433605 }}</ref>

Mutagenesis of [[Biology:Protein kinase C|protein kinase C]] phosphorylation sites in TRPM8 (wild type serines and threonines replaced by alanine in mutants) reduces the desensitizing response.<ref name="pmid16380208">{{cite journal | vauthors = Abe J, Hosokawa H, Sawada Y, Matsumura K, Kobayashi S | title = Ca2+-dependent PKC activation mediates menthol-induced desensitization of transient receptor potential M8 | journal = Neuroscience Letters | volume = 397 | issue = 1–2 | pages = 140–4 | year = 2006 | pmid = 16380208 | doi = 10.1016/j.neulet.2005.12.005 | s2cid = 23638727 }}</ref>

[[Chemistry:Caryophyllene|Caryophyllene]] inhibits TRPM8, which helps mammals to improve cold tolerance at low ambient temperatures.<ref>{{cite journal | vauthors = Zhou W, Yang S, Li B, Nie Y, Luo A, Huang G, Liu X, Lai R, Wei F | display-authors = 6 | title = Why wild giant pandas frequently roll in horse manure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 51 | pages = 32493–32498 | date = December 2020 | pmid = 33288697 | pmc = 7768701 | doi = 10.1073/pnas.2004640117 | bibcode = 2020PNAS..11732493Z | doi-access = free }}</ref>

=== Cross-desensitization===
Cliff ''et al.'', 1994, performed a study to discover more about the properties of the menthol receptor and whether menthol had the ability to cross-desensitize with other chemical irritant receptors. [[Chemistry:Capsaicin|Capsaicin]] was known to cross-desensitize with other irritant agonists, where the same information was not known about menthol. The study involved subjects swishing either menthol or capsaicin for an extended time at regular intervals. There were three significant conclusions about cross-desensitizing: 1) Both chemicals self-desensitize, 2) menthol receptors can desensitize in response to [[Chemistry:Capsaicin|capsaicin]], and, most novelly, 3) capsaicin receptors are sensitized in response to menthol.<ref name="pmid8700951">{{cite journal | vauthors = Cliff MA, Green BG | title = Sensitization and desensitization to capsaicin and menthol in the oral cavity: interactions and individual differences | journal = Physiology & Behavior | volume = 59 | issue = 3 | pages = 487–94 | date = March 1996 | pmid = 8700951 | doi = 10.1016/0031-9384(95)02089-6 | s2cid = 45406823 }}</ref>

== Ligands ==

=== Agonists ===
In a search for compounds that activated the TRPM8 cold receptor, compounds that produce a cooling-sensation were sought out from the fragrance industries. Of 70 relevant compounds, the following 10 produced the associated [Ca2+]-increase response in mTRPM8-transfected HEK293 cells used to identify agonists. Experimentally identified and commonly utilized agonists of the menthol receptor include [[Chemistry:Linalool|linalool]], [[Chemistry:Geraniol|geraniol]], hydroxy-[[Chemistry:Citronellal|citronellal]], [[Chemistry:Icilin|icilin]], WS-12, Frescolat MGA, Frescolat ML, [[Chemistry:P-Menthane-3,8-diol|PMD 38]], Coolact P, M8-Ag and [[Chemistry:Menthoxypropanediol|Cooling Agent 10]].<ref name="pmid14757700"/><ref name="Patel_2014" /> Traditionally used agonists include [[Chemistry:Menthol|menthol]]<ref>{{cite journal | vauthors = Eccles R | title = Menthol and related cooling compounds | journal = The Journal of Pharmacy and Pharmacology | volume = 46 | issue = 8 | pages = 618–30 | date = August 1994 | pmid = 7529306 | doi = 10.1111/j.2042-7158.1994.tb03871.x | s2cid = 20568911 }}</ref> and [[Chemistry:Borneol|borneol]].<ref>{{cite journal | vauthors = Chen GL, Lei M, Zhou LP, Zeng B, Zou F | title = Borneol Is a TRPM8 Agonist that Increases Ocular Surface Wetness | journal = PLOS ONE | volume = 11 | issue = 7 | pages = e0158868 | date = 2016 | pmid = 27448228 | doi = 10.1371/journal.pone.0158868 | pmc = 4957794 | bibcode = 2016PLoSO..1158868C | doi-access = free }}</ref>

===Antagonists===
BCTC, thio-BCTC, [[Chemistry:Capsazepine|capsazepine]] and M8-An<ref name="Patel_2014b">{{cite journal | vauthors = Patel R, Gonçalves L, Newman R, Jiang FL, Goldby A, Reeve J, Hendrick A, Teall M, Hannah D, Almond S, Brice N, Dickenson AH | display-authors = 6 | title = Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 349 | issue = 1 | pages = 47–55 | date = April 2014 | pmid = 24472724 | doi = 10.1124/jpet.113.211243 | s2cid = 10407715 }}</ref> were identified as [[Biology:Receptor antagonist|antagonist]]s of the TRPM8 receptor. These antagonists physically block the receptor for cold and menthol, by binding to the S1-S4 voltage-sensing domain, preventing response.<ref name="pmid14757700"/>

* [[Chemistry:AMG-333|AMG-333]]
* RQ-00434739
* [[Chemistry:RQ-00203078|RQ-00203078]]
* [[Chemistry:PF-05105679|PF-05105679]] cas: [1398583-31-7].
* M8 B
* AMTB
* 5-benzyloxytryptamine<ref>{{cite journal | vauthors = DeFalco J, Steiger D, Dourado M, Emerling D, Duncton MA | title = 5-benzyloxytryptamine as an antagonist of TRPM8 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 23 | pages = 7076–9 | date = December 2010 | pmid = 20965726 | doi = 10.1016/j.bmcl.2010.09.099 }}</ref>
* [[Chemistry:Anandamide|Anandamide]]<ref name="De_Petrocellis_2007">{{cite journal | vauthors = De Petrocellis L, Starowicz K, Moriello AS, Vivese M, Orlando P, Di Marzo V | title = Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB(1) receptors and endovanilloids | journal = Experimental Cell Research | volume = 313 | issue = 9 | pages = 1911–1920 | date = May 2007 | pmid = 17428469 | doi = 10.1016/j.yexcr.2007.01.008 }}</ref>
* [[Chemistry:N-Arachidonoyl dopamine|N-Arachidonoyl dopamine]]<ref name="De_Petrocellis_2007" />
* [[Biology:Tetrahydrocannabinol|Tetrahydrocannabinol]]<ref name="De_Petrocellis_2008">{{cite journal | vauthors = De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V | title = Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 325 | issue = 3 | pages = 1007–1015 | date = June 2008 | pmid = 18354058 | doi = 10.1124/jpet.107.134809 | s2cid = 5997192 }}</ref>
* [[Chemistry:Tetrahydrocannabinolic acid|Tetrahydrocannabinolic acid]]<ref name="De_Petrocellis_2008" />
* [[Chemistry:Cannabidiol|Cannabidiol]]<ref name="De_Petrocellis_2008" />
* [[Chemistry:Cannabidiolic acid|Cannabidiolic acid]]<ref name="De_Petrocellis_2008" />
*[[Chemistry:Cannabigerol|Cannabigerol]]<ref name="De_Petrocellis_2008" />
*[[Chemistry:Tetrahydrocannabivarin|Tetrahydrocannabivarin]]<ref name="De_Petrocellis_2011">{{cite journal | vauthors = De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, Di Marzo V | display-authors = 6 | title = Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes | journal = British Journal of Pharmacology | volume = 163 | issue = 7 | pages = 1479–1494 | date = August 2011 | pmid = 21175579 | pmc = 3165957 | doi = 10.1111/j.1476-5381.2010.01166.x }}</ref>
*Tetrahydrocannabivarin Acid<ref name="De_Petrocellis_2011" />
*[[Chemistry:Cannabidivarin|Cannabidivarin]]<ref name="De_Petrocellis_2011" />
*[[Chemistry:Cannabigerolic acid|Cannabigerolic acid]]<ref name="De_Petrocellis_2011" />
*[[Chemistry:Cannabigerovarin|Cannabigerovarin]]<ref name="De_Petrocellis_2011" />
*[[Chemistry:Cannabichromene|Cannabichromene]]<ref name="De_Petrocellis_2011" />
*[[Chemistry:Cannabinol|Cannabinol]]<ref name="De_Petrocellis_2011" />

== Clinical significance ==
Cold-patches have traditionally been used to induce analgesia or relief in pain which is caused as result of traumatic injuries.<ref>{{cite journal | vauthors = Sikandar S, Patel R, Patel S, Sikander S, Bennett DL, Dickenson AH | title = Genes, molecules and patients--emerging topics to guide clinical pain research | journal = European Journal of Pharmacology | volume = 716 | issue = 1–3 | pages = 188–202 | date = September 2013 | pmid = 23500200 | pmc = 3793871 | doi = 10.1016/j.ejphar.2013.01.069 }}</ref> 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 [[Chemistry:Menthol|menthol]]) or when ambient temperatures drop below approximately 26&nbsp;°C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons of [[Biology:Afferent nerve fiber|afferent nerve fiber]]s.<ref name="pmid17538622">{{cite journal | vauthors = Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D | display-authors = 6 | title = The menthol receptor TRPM8 is the principal detector of environmental cold | journal = Nature | volume = 448 | issue = 7150 | pages = 204–8 | date = July 2007 | pmid = 17538622 | doi = 10.1038/nature05910 | s2cid = 4427901 | bibcode = 2007Natur.448..204B }}</ref>

Three independent research groups have reported that mice lacking functional TRPM8 gene expression are severely impaired in their ability to detect [[Physics:Cold|cold]] temperatures.<ref name="pmid17705869">{{cite journal | vauthors = Daniels RL, McKemy DD | title = Mice left out in the cold: commentary on the phenotype of TRPM8-nulls | journal = Molecular Pain | volume = 3 | issue = 1 | pages = 23 | date = August 2007 | pmid = 17705869 | pmc = 1988789 | doi = 10.1186/1744-8069-3-23 | doi-access = free }}</ref> 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.<ref name="Patel_2014" /><ref name="Patel_2014b" />

Low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions,<ref name="pmid16920620">{{cite journal | vauthors = Proudfoot CJ, Garry EM, Cottrell DF, Rosie R, Anderson H, Robertson DC, Fleetwood-Walker SM, Mitchell R | display-authors = 6 | title = Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain | journal = Current Biology | volume = 16 | issue = 16 | pages = 1591–605 | date = August 2006 | pmid = 16920620 | doi = 10.1016/j.cub.2006.07.061 | s2cid = 18467791 | doi-access = free | hdl = 20.500.11820/40bf3f19-c65f-4ffe-a2a3-b6c30357701d | hdl-access = free }}</ref> whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers.<ref name="pmid14985268"/>

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.<ref name="pmid17481392">{{cite journal | vauthors = Colburn RW, Lubin ML, Stone DJ, Wang Y, Lawrence D, D'Andrea MR, Brandt MR, Liu Y, Flores CM, Qin N | display-authors = 6 | title = Attenuated cold sensitivity in TRPM8 null mice | journal = Neuron | volume = 54 | issue = 3 | pages = 379–86 | date = May 2007 | pmid = 17481392 | doi = 10.1016/j.neuron.2007.04.017 | s2cid = 17703702 | doi-access = free }}</ref> Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models.<ref name="pmid18562636">{{cite journal | vauthors = Lashinger ES, Steiginga MS, Hieble JP, Leon LA, Gardner SD, Nagilla R, Davenport EA, Hoffman BE, Laping NJ, Su X | display-authors = 6 | title = AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome | journal = American Journal of Physiology. Renal Physiology | volume = 295 | issue = 3 | pages = F803-10 | date = September 2008 | pmid = 18562636 | doi = 10.1152/ajprenal.90269.2008 }}</ref><ref name="Patel_2014b" />

TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes.<ref name="pmid16519806">{{cite journal | vauthors = Mukerji G, Yiangou Y, Corcoran SL, Selmer IS, Smith GD, Benham CD, Bountra C, Agarwal SK, Anand P | display-authors = 6 | title = Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations | journal = BMC Urology | volume = 6 | pages = 6 | date = March 2006 | pmid = 16519806 | pmc = 1420318 | doi = 10.1186/1471-2490-6-6 | doi-access = free }}</ref> 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.<ref name="urlDendreon: Targeting Cancer, Transforming Lives">{{cite web|url=http://investor.dendreon.com/ReleaseDetail.cfm?ReleaseID=174120&Header=News |title=Dendreon: Targeting Cancer, Transforming Lives |date=2005-09-21 |publisher=Dendreon Corporation |archive-url=https://web.archive.org/web/20081028185621/http://investor.dendreon.com/ReleaseDetail.cfm?ReleaseID=174120&Header=News |archive-date=October 28, 2008 |access-date=2008-10-31 |url-status=dead }}</ref>

=== Role in cancer ===
TRPM8 channels may be a target for treating [[Medicine:Prostate cancer|prostate cancer]]. TRPM8 is an [[Biology:Androgen|androgen]] dependent Ca<sup>2+</sup> channel necessary for [[Medicine:Prostate cancer|prostate cancer]] cells to survive and grow. Immunofluorescence showed expression of the TRPM8 protein in the ER and plasma membrane of the androgen-responsive [[Biology:LNCaP|LNCaP]] cell line. TRPM8 was expressed in androgen-insensitive cells, but it was not shown to be needed for their survival. By knockout of TRPM8 with siRNAs targeting TRPM8 [[Biology:MRNA|mRNA]]s, the necessity of the TRPM8 receptor was shown in the androgen-dependent cancer cells. This has useful implications in terms of [[Biology:Gene therapy|gene therapy]], as there are so few treatment options for men with prostate cancer. As an androgen-regulated protein whose function is lost as cancer develops in cells, the TRPM8 protein seems to be especially critical in regulating calcium levels and has recently been proposed as the focus of new drugs used to treat prostate cancer.<ref name="pmid15548706">{{cite journal | vauthors = Zhang L, Barritt GJ | title = Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells | journal = Cancer Research | volume = 64 | issue = 22 | pages = 8365–73 | date = November 2004 | pmid = 15548706 | doi = 10.1158/0008-5472.CAN-04-2146 | doi-access = free }}</ref>

== See also ==
*[[Biology:Endocannabinoid system|Endocannabinoid system]]
*[[Biology:TRPM|TRPM]]
* [[Chemistry:Ruthenium red|Ruthenium red]]

== References ==
{{Reflist|30em}}

== Further reading ==
{{Refbegin | 2}}
* {{cite journal | vauthors = Clapham DE, Julius D, Montell C, Schultz G | title = International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 427–50 | date = December 2005 | pmid = 16382100 | doi = 10.1124/pr.57.4.6 | s2cid = 17936350 }}
* {{cite book | vauthors = Voets T, Owsianik G, Nilius B | title = Transient Receptor Potential (TRP) Channels | chapter = TRPM8 | volume = 179 | issue = 179 | pages = 329–44 | year = 2007 | pmid = 17217067 | doi = 10.1007/978-3-540-34891-7_20 | isbn = 978-3-540-34889-4 | series = Handbook of Experimental Pharmacology }}
{{Refend}}

== External links ==
* {{MeshName|TRPM8+protein,+human}}

{{NLM content}}
{{Ion channels|g4}}
{{Transient receptor potential channel modulators}}

[[Category:Ion channels]]

{{Sourceattribution|TRPM8}}