Target Information
| Target General Information | Top | |||||
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| Target ID |
T41955
(Former ID: TTDS00507)
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| Target Name |
Long transient receptor potential channel 8 (TRPM8)
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| Synonyms |
Trp-p8; Transient receptor potential-p8; Transient receptor potential cation channel subfamily M member 8; TRPP8; TRPM8; LTrpC6
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| Gene Name |
TRPM8
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Upper respiratory tract disorder [ICD-11: CA0Z] | |||||
| 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.
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| BioChemical Class |
Transient receptor potential catioin channel
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| UniProt ID | ||||||
| Sequence |
MSFRAARLSMRNRRNDTLDSTRTLYSSASRSTDLSYSESDLVNFIQANFKKRECVFFTKD
SKATENVCKCGYAQSQHMEGTQINQSEKWNYKKHTKEFPTDAFGDIQFETLGKKGKYIRL SCDTDAEILYELLTQHWHLKTPNLVISVTGGAKNFALKPRMRKIFSRLIYIAQSKGAWIL TGGTHYGLMKYIGEVVRDNTISRSSEENIVAIGIAAWGMVSNRDTLIRNCDAEGYFLAQY LMDDFTRDPLYILDNNHTHLLLVDNGCHGHPTVEAKLRNQLEKYISERTIQDSNYGGKIP IVCFAQGGGKETLKAINTSIKNKIPCVVVEGSGQIADVIASLVEVEDALTSSAVKEKLVR FLPRTVSRLPEEETESWIKWLKEILECSHLLTVIKMEEAGDEIVSNAISYALYKAFSTSE QDKDNWNGQLKLLLEWNQLDLANDEIFTNDRRWESADLQEVMFTALIKDRPKFVRLFLEN GLNLRKFLTHDVLTELFSNHFSTLVYRNLQIAKNSYNDALLTFVWKLVANFRRGFRKEDR NGRDEMDIELHDVSPITRHPLQALFIWAILQNKKELSKVIWEQTRGCTLAALGASKLLKT LAKVKNDINAAGESEELANEYETRAVELFTECYSSDEDLAEQLLVYSCEAWGGSNCLELA VEATDQHFIAQPGVQNFLSKQWYGEISRDTKNWKIILCLFIIPLVGCGFVSFRKKPVDKH KKLLWYYVAFFTSPFVVFSWNVVFYIAFLLLFAYVLLMDFHSVPHPPELVLYSLVFVLFC DEVRQWYVNGVNYFTDLWNVMDTLGLFYFIAGIVFRLHSSNKSSLYSGRVIFCLDYIIFT LRLIHIFTVSRNLGPKIIMLQRMLIDVFFFLFLFAVWMVAFGVARQGILRQNEQRWRWIF RSVIYEPYLAMFGQVPSDVDGTTYDFAHCTFTGNESKPLCVELDEHNLPRFPEWITIPLV CIYMLSTNILLVNLLVAMFGYTVGTVQENNDQVWKFQRYFLVQEYCSRLNIPFPFIVFAY FYMVVKKCFKCCCKEKNMESSVCCFKNEDNETLAWEGVMKENYLVKINTKANDTSEEMRH RFRQLDTKLNDLKGLLKEIANKIK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T60XJI | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Menthol | Drug Info | Approved | Throat irritation | [2], [3] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | D-3263 | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
| 2 | PF-05105679 | Drug Info | Phase 1 | Pain | [5] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Activator | [+] 14 Activator drugs | + | ||||
| 1 | Menthol | Drug Info | [1] | |||
| 2 | CPS125 | Drug Info | [11] | |||
| 3 | eucalyptol | Drug Info | [12] | |||
| 4 | frescolat MGA | Drug Info | [13] | |||
| 5 | frescolat ML | Drug Info | [13] | |||
| 6 | geraniol | Drug Info | [13] | |||
| 7 | hydroxycitronellal | Drug Info | [13] | |||
| 8 | icilin | Drug Info | [14] | |||
| 9 | isopulegol | Drug Info | [13] | |||
| 10 | PMD38 | Drug Info | [13] | |||
| 11 | WS-12 | Drug Info | [11] | |||
| 12 | WS-23 | Drug Info | [13] | |||
| 13 | WS-3 | Drug Info | [13] | |||
| 14 | WS-5 | Drug Info | [11] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | D-3263 | Drug Info | [6] | |||
| 2 | PF-05105679 | Drug Info | [5] | |||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | 2-(5-fluoro-1H-indol-3-yl)ethanamine | Drug Info | [7] | |||
| 2 | 2-(7-(benzyloxy)-1H-indol-3-yl)ethanamine | Drug Info | [7] | |||
| 3 | 5-Benzyloxytryptamine | Drug Info | [7] | |||
| 4 | 5-METHOXYTRYPTAMINE | Drug Info | [7] | |||
| 5 | Perillaldehyde | Drug Info | [17] | |||
| Blocker (channel blocker) | [+] 7 Blocker (channel blocker) drugs | + | ||||
| 1 | 2-APB | Drug Info | [8] | |||
| 2 | ACAA | Drug Info | [9] | |||
| 3 | AMTB | Drug Info | [10] | |||
| 4 | M8-B | Drug Info | [15] | |||
| 5 | NADA | Drug Info | [9] | |||
| 6 | PBMC | Drug Info | [16] | |||
| 7 | thio-BCTC | Drug Info | [13] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | RQ-00203078 | Drug Info | [9] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Inflammatory mediator regulation of TRP channels | hsa04750 | Affiliated Target |
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| Class: Organismal Systems => Sensory system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.51E-01 | Radiality | 1.20E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 3.00E+00 | Topological coefficient | 7.50E-01 | Eccentricity | 14 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Inflammatory mediator regulation of TRP channels | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | TRP channels | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009 May;64(5):807-10. | |||||
| REF 2 | URL: 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 3 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022029. | |||||
| REF 4 | ClinicalTrials.gov (NCT00839631) Dose Escalation Study of EC D-3263 HCl in Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 5 | Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther. 2014 Nov;351(2):259-69. | |||||
| REF 6 | Best 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. | |||||
| REF 7 | 5-benzyloxytryptamine as an antagonist of TRPM8. Bioorg Med Chem Lett. 2010 Dec 1;20(23):7076-9. | |||||
| REF 8 | Effects 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 9 | URL: 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 10 | AMTB, 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 11 | Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. J Pharm Pharm Sci. 2010;13(2):242-53. | |||||
| REF 12 | Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002 Mar 7;416(6876):52-8. | |||||
| REF 13 | Characterization 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. | |||||
| REF 14 | Evolution of thermal response properties in a cold-activated TRP channel. PLoS One. 2009 May 29;4(5):e5741. | |||||
| REF 15 | Pharmacological 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 16 | Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS One. 2011;6(9):e25894. | |||||
| REF 17 | Taste-guided identification of high potency TRPA1 agonists from Perilla frutescens. Bioorg Med Chem. 2009 Feb 15;17(4):1636-9. | |||||
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