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TRPM8

Family: Transient Receptor Potential channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Ion Selectivity and Conductance
Voltage Dependence
Activators
Pore Blockers
Tissue Distribution
Functional Assays
Physiological Functions
Phenotypes, Alleles and Disease Models
Gene Expression and Pathophysiology
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1104 2q37.1 TRPM8 transient receptor potential cation channel, subfamily M, member 8 8
Mouse 6 1 1104 1 D Trpm8 transient receptor potential cation channel, subfamily M, member 8 6
Rat 6 1 1104 9q35 Trpm8 transient receptor potential cation channel, subfamily M, member 8 5
Previous and Unofficial Names
Trp-p8
LTrpC6
Cmr1
CMR1
TRP-p8
cold menthol receptor 1
cold/menthol receptor 1
transient receptor potential cation channel subfamily M member 8
transient receptor potential cation channel, subfamily M, member 8
TRPP8
Database Links
ChEMBL Target 101263 (Rn)
DrugBank Target 2162 (Hs)
Ensembl ENSG00000144481 (Hs), ENSMUSG00000036251 (Mm), ENSRNOG00000019035 (Rn)
Entrez Gene 79054 (Hs), 171382 (Mm), 171384 (Rn)
GeneCards TRPM8 (Hs)
GenitoUrinary Development Molecular Anatomy Project Trpm8 (Mm)
HomoloGene 23433 (Hs)
Human Protein Reference Database 09454 (Hs)
InterPro Q7Z2W7 (Hs), Q8R4D5 (Mm), Q8R455 (Rn)
KEGG Gene hsa:79054 (Hs), mmu:171382 (Mm), rno:171384 (Rn)
OMIM 620053 (Hs)
PharmGKB Gene PA38270 (Hs)
PhosphoSitePlus Q7Z2W7 (Hs), Q8R4D5 (Mm)
Protein Ontology (PRO) PRO:000001719 (Hs)
RefSeq Nucleotide NM_024080 (Hs), NM_134252 (Mm), NM_134371 (Rn)
RefSeq Protein NP_076985 (Hs), NP_599013 (Mm), NP_599198 (Rn)
TreeFam ENSG00000144481 (Hs), ENSMUSG00000036251 (Mm), ENSRNOG00000019035 (Rn)
UniGene Hs. 366053 (Hs)
UniProt Q7Z2W7 (Hs), Q8R4D5 (Mm), Q8R455 (Rn)
Wikipedia TRPM8
Transient Receptor Potential channels
Search for 3D structures on the PDB
Search by keyword: Transient Receptor Potential channels TRPM8 Search by accession number: Q8R4D5, Q7Z2W7, Q8R455
Ion Selectivity and Conductance
Species:  Mouse
Rank order:  Cs+ > K+ > Na+
References:  6
Ion Selectivity and Conductance Comments
Single channel conductance (rat) = 83 pS [5]
PCa:PNa ratio = 0.97-3.3 [5-6]
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  25.0 – 200.0 1.0 – 15.0 9 HEK 293 cells transiently transfected with TRPM8. Human
Inactivation  - -
Comments  Cold-induced activation of TRPM8 is the result of a drastic leftward shift of the voltage dependence of activation (7.3 mV °C-1).
Other chemical activators (Human)
agonist activities are temperature dependent and potentiated by cooling
Physical activators (Human)
depolarization (V½ ~ +50 mV at 15°C), cooling (< 22-26°C)
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
icilin Mm 6.7 – 6.9 pEC50 - Physiological 2-3
icilin Rn 6.4 pEC50 - -60.0 5
frescolat ML Mm 5.5 pEC50 - Physiological 3
menthol Mm 5.4 pEC50 - Physiological 3
WS-3 Mm 5.4 pEC50 - Physiological 3
frescolat MGA Mm 5.3 pEC50 - Physiological 3
cooling agent 10 Mm 5.2 pEC50 - Physiological 3
(+)-menthol Mm 4.8 pEC50 - Physiological 3
menthol Hs 4.6 pEC50 - -120.0 – 160.0 9
PMD38 Mm 4.5 pEC50 - Physiological 3
WS-23 Mm 4.4 pEC50 - Physiological 3
coolact P Mm 4.2 pEC50 - Physiological 3
menthol Rn 4.2 – 4.1 pEC50 - -60.0 5
menthol Mm 4.0 pEC50 - Physiological 2
eucalyptol Rn 2.5 pEC50 - -60.0 5
geraniol Mm 2.2 pEC50 - Physiological 3
linalool Mm 2.2 pEC50 - Physiological 3
eucalyptol Mm 2.1 pEC50 - Physiological 3
hydroxycitronellal Mm 1.7 pEC50 - Physiological 3
View species-specific activator tables
Activator Comments
TRPM8 is also activated by cold (<26°C)[1,5] and it has been proposed that menthol acts by modulating the temperature sensitivity of the receptor [9].

Decreasing intracellular pH also modulates activation of the receptor by cold and icilin, but not menthol (IC50 at pH 7.2-7.6) [2].
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
BCTC Mm 6.1 pIC50 - Physiological 3
thio-BCTC Mm 5.5 pIC50 - Physiological 3
2-APB Mm 4.9 – 5.1 pIC50 - 100.0 – -100.0 4
capsazepine Mm 4.7 pIC50 - Physiological 3
Pore Blocker Comments
It is unknown whether these compounds are pore blockers or gating inhibitors.

Explore drug-target interactions for this set of compounds using iPHACE

Tissue Distribution
Prostate
Species:  Human
Technique:  Northern Blot
References:  8
Prostate, testis, bladder > breast, thymus
Species:  Human
Technique:  RT-PCR
References:  8
Prostate, breast
Species:  Human
Technique:  In situ hybridisation
References:  8
Dorsal root ganglion
Species:  Mouse
Technique:  Northern Blot
References:  6
Dorsal root ganglion, trigeminal ganglion
Species:  Mouse
Technique:  In situ hybridisation
References:  6
Dorsal root ganglia, trigeminal ganglia
Species:  Rat
Technique:  Northern Blot
References:  5
Dorsal root ganglia, trigeminal ganglia
Species:  Rat
Technique:  In situ hybridisation
References:  5
Dorsal root ganglion, testis, prostate, bladder
Species:  Rat
Technique:  RT-PCR
References:  7
Functional Assays
Patch-clamp analysis (whole-cell and single-channel recordings), intracellular Ca2+ imaging.
Species:  Mouse
Tissue:  CHO cells transfected with a TRPM8 vector.
Response measured:  Activation by cold, menthol etc.
References:  6
Patch-clamp analysis (whole-cell and single-channel recordings).
Species:  Human
Tissue:  HEK cells transfected with a TRPM8 vector.
Response measured:  Activation by cold, menthol etc.
References:  9
Patch-clamp analysis (whole-cell and single-channel recordings), intracellular Ca2+ imaging.
Species:  Rat
Tissue:  HEK cells transfected with a TRPM8 vector
Response measured:  Activation by cold, menthol icilin etc.
References:  5
Physiological Functions
A cold and menthol receptor. Integration of thermal and chemical stimuli.
Species:  None
Tissue:  Dorsal root and trigeminal ganglia.
References:  5-6
Physiological Functions Comments
These functions have been found in both rats and mice.
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:2181435  MP:0004811 abnormal neuron physiology PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6		 MGI:2181435  MP:0004811 abnormal neuron physiology PMID: 17481391 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:2181435  MP:0002736 abnormal nociception after inflammation PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6		 MGI:2181435  MP:0002736 abnormal nociception after inflammation PMID: 17481391 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:2181435  MP:0001970 abnormal pain threshold PMID: 17481392 
Trpm8tm1Jul Trpm8tm1Jul/Trpm8tm1Jul
involves: 129P2/OlaHsd * C57BL/6		 MGI:2181435  MP:0003663 abnormal thermosensation PMID: 17538622 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:2181435  MP:0003663 abnormal thermosensation PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6		 MGI:2181435  MP:0003663 abnormal thermosensation PMID: 17481391 
Trpm8tm1Jul Trpm8tm1Jul/Trpm8tm1Jul
involves: 129P2/OlaHsd * C57BL/6		 MGI:2181435  MP:0001973 increased thermal nociceptive threshold PMID: 17538622 
Trpm8tm1Lex Trpm8tm1Lex/Trpm8tm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:2181435  MP:0001973 increased thermal nociceptive threshold PMID: 17481392 
Trpm8tm1Apat Trpm8tm1Apat/Trpm8tm1Apat
involves: 129S1/Sv * C57BL/6		 MGI:2181435  MP:0001973 increased thermal nociceptive threshold PMID: 17481391 
Gene Expression and Pathophysiology
Up-regulated in adenocarcinomas.
Tissue or cell type:  Prostate as well as breast, colon, lung and skin
Pathophysiology:  Adenocarcinoma
Species:  Human
Technique:  In-situ hybridisation
References:  8

REFERENCES

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1. Aarts, M; Iihara, K; Wei, WL; Xiong, ZG; Arundine, M; Cerwinski, W; MacDonald, JF; Tymianski, M. (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell, 115 (7): 863-77. [PMID:14697204]

2. Andersson, DA; Chase, HW; Bevan, S. (2004) TRPM8 activation by menthol, icilin, and cold is differentially modulated by intracellular pH. J. Neurosci., 24 (23): 5364-9. [PMID:15190109]

3. Behrendt, HJ; Germann, T; Gillen, C; Hatt, H; Jostock, R. (2004) 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., 141 (4): 737-45. [PMID:14757700]

4. Hu, HZ; Gu, Q; Wang, C; Colton, CK; Tang, J; Kinoshita-Kawada, M; Lee, LY; Wood, JD; Zhu, MX. (2004) 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J. Biol. Chem., 279 (34): 35741-8. [PMID:15194687]

5. McKemy, DD; Neuhausser, WM; Julius, D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 416 (6876): 52-8. [PMID:11882888]

6. Peier, AM; Moqrich, A; Hergarden, AC; Reeve, AJ; Andersson, DA; Story, GM; Earley, TJ; Dragoni, I; McIntyre, P; Bevan, S; Patapoutian, A. (2002) A TRP channel that senses cold stimuli and menthol. Cell, 108 (5): 705-15. [PMID:11893340]

7. Stein, RJ; Santos, S; Nagatomi, J; Hayashi, Y; Minnery, BS; Xavier, M; Patel, AS; Nelson, JB; Futrell, WJ; Yoshimura, N; Chancellor, MB; De Miguel, F. (2004) Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J. Urol., 172 (3): 1175-8. [PMID:15311065]

8. Tsavaler, L; Shapero, MH; Morkowski, S; Laus, R. (2001) Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res., 61 (9): 3760-9. [PMID:11325849]

9. Voets, T; Droogmans, G; Wissenbach, U; Janssens, A; Flockerzi, V; Nilius, B. (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature, 430 (7001): 748-54. [PMID:15306801]

To cite this database page, please use the following:

David E. Clapham, Bernd Nilius, Grzegorz Owsianik.
Transient Receptor Potential channels: TRPM8. Last modified on 24/11/2011. Accessed on 24/05/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=500.


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