Target Information

Target General Infomation
Target ID
T41955
Former ID
TTDS00507
Target Name
TRPM8 protein
Gene Name
TRPM8
Synonyms
LTrpC6; Long transient receptor potential channel 6; TRPP8; Transient receptor potential-p8; Trp-p8; Transient receptor potential cation channel subfamily M member 8; TRPM8
Target Type
Successful
Disease Neuropathic pain [ICD9: 356.0, 356.8; ICD10: G64, G90.0]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Throat irritation [ICD9: 478.29; ICD10: J39.2]
Function
Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel.
BioChemical Class
Transient receptor potential catioin channel
Target Validation
T41955
UniProt ID
Q7Z2W7
Sequence
MSFRAARLSMRNRRNDTLDSTRTLYSSASRSTDLSYSESDLVNFIQANFKKRECVFFTKD
SKATENVCKCGYAQSQHMEGTQINQSEKWNYKKHTKEFPTDAFGDIQFETLGKKGKYIRL
SCDTDAEILYELLTQHWHLKTPNLVISVTGGAKNFALKPRMRKIFSRLIYIAQSKGAWIL
TGGTHYGLMKYIGEVVRDNTISRSSEENIVAIGIAAWGMVSNRDTLIRNCDAEGYFLAQY
LMDDFTRDPLYILDNNHTHLLLVDNGCHGHPTVEAKLRNQLEKYISERTIQDSNYGGKIP
IVCFAQGGGKETLKAINTSIKNKIPCVVVEGSGQIADVIASLVEVEDALTSSAVKEKLVR
FLPRTVSRLPEEETESWIKWLKEILECSHLLTVIKMEEAGDEIVSNAISYALYKAFSTSE
QDKDNWNGQLKLLLEWNQLDLANDEIFTNDRRWESADLQEVMFTALIKDRPKFVRLFLEN
GLNLRKFLTHDVLTELFSNHFSTLVYRNLQIAKNSYNDALLTFVWKLVANFRRGFRKEDR
NGRDEMDIELHDVSPITRHPLQALFIWAILQNKKELSKVIWEQTRGCTLAALGASKLLKT
LAKVKNDINAAGESEELANEYETRAVELFTECYSSDEDLAEQLLVYSCEAWGGSNCLELA
VEATDQHFIAQPGVQNFLSKQWYGEISRDTKNWKIILCLFIIPLVGCGFVSFRKKPVDKH
KKLLWYYVAFFTSPFVVFSWNVVFYIAFLLLFAYVLLMDFHSVPHPPELVLYSLVFVLFC
DEVRQWYVNGVNYFTDLWNVMDTLGLFYFIAGIVFRLHSSNKSSLYSGRVIFCLDYIIFT
LRLIHIFTVSRNLGPKIIMLQRMLIDVFFFLFLFAVWMVAFGVARQGILRQNEQRWRWIF
RSVIYEPYLAMFGQVPSDVDGTTYDFAHCTFTGNESKPLCVELDEHNLPRFPEWITIPLV
CIYMLSTNILLVNLLVAMFGYTVGTVQENNDQVWKFQRYFLVQEYCSRLNIPFPFIVFAY
FYMVVKKCFKCCCKEKNMESSVCCFKNEDNETLAWEGVMKENYLVKINTKANDTSEEMRH
RFRQLDTKLNDLKGLLKEIANKIK
Drugs and Mode of Action
Drug(s) Menthol Drug Info Approved Throat irritation [1], [2]
D-3263 Drug Info Phase 1 Solid tumours [3]
PF-05105679 Drug Info Phase 1 Pain [4]
Inhibitor 2-(5-fluoro-1H-indol-3-yl)ethanamine Drug Info [5]
2-(7-(benzyloxy)-1H-indol-3-yl)ethanamine Drug Info [5]
5-Benzyloxytryptamine Drug Info [5]
5-METHOXYTRYPTAMINE Drug Info [5]
PERILLALDEHYDE Drug Info [6]
Blocker (channel blocker) 2-APB Drug Info [7]
ACAA Drug Info [8]
AMTB Drug Info [9]
M8-B Drug Info [10]
NADA Drug Info [8]
PBMC Drug Info [11]
thio-BCTC Drug Info [12]
Activator cooling agent 10 Drug Info [12]
CPS125 Drug Info [13]
eucalyptol Drug Info [14]
frescolat MGA Drug Info [12]
frescolat ML Drug Info [12]
geraniol Drug Info [12]
hydroxycitronellal Drug Info [12]
icilin Drug Info [15]
isopulegol Drug Info [12]
linalool Drug Info [12]
Menthol Drug Info [16]
PMD38 Drug Info [12]
WS-12 Drug Info [13]
WS-23 Drug Info [12]
WS-3 Drug Info [12]
WS-5 Drug Info [13]
Modulator D-3263 Drug Info [17]
PF-05105679 Drug Info [4]
Antagonist RQ-00203078 Drug Info [8]
Pathways
KEGG Pathway Inflammatory mediator regulation of TRP channels
Reactome TRP channels
References
REF 1FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022029.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2471).
REF 3ClinicalTrials.gov (NCT00839631) Dose Escalation Study of EC D-3263 HCl in Advanced Solid Tumors. U.S. National Institutes of Health.
REF 4Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther. 2014 Nov;351(2):259-69.
REF 5Bioorg Med Chem Lett. 2010 Dec 1;20(23):7076-9. Epub 2010 Sep 22.5-benzyloxytryptamine as an antagonist of TRPM8.
REF 6Bioorg Med Chem. 2009 Feb 15;17(4):1636-9. Epub 2008 Dec 30.Taste-guided identification of high potency TRPA1 agonists from Perilla frutescens.
REF 7Effects of antagonists and heat on TRPM8 channel currents in dorsal root ganglion neuron activated by nociceptive cold stress and menthol. Neurochem Res. 2012 Feb;37(2):314-20.
REF 8(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 500).
REF 9AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am J Physiol Renal Physiol. 2008 Sep;295(3):F803-10.
REF 10Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J Neurosci. 2012 Feb 8;32(6):2086-99.
REF 11Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS One. 2011;6(9):e25894.
REF 12Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br J Pharmacol. 2004 Feb;141(4):737-45. Epub 2004Feb 2.
REF 13Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. J Pharm Pharm Sci. 2010;13(2):242-53.
REF 14Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002 Mar 7;416(6876):52-8. Epub 2002 Feb 10.
REF 15Evolution of thermal response properties in a cold-activated TRP channel. PLoS One. 2009 May 29;4(5):e5741.
REF 16TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009 May;64(5):807-10. Epub 2009 Feb 13.
REF 17Best of the 2009 AUA Annual Meeting: Highlights from the 2009 Annual Meeting of the American Urological Association, April 25-30, 2009, Chicago, IL. Rev Urol. 2009 Spring; 11(2): 82-107.

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