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Q7Z2W7 (TRPM8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Transient receptor potential cation channel subfamily M member 8
Alternative name(s):
Long transient receptor potential channel 6
Short name=LTrpC-6
Short name=LTrpC6
Transient receptor potential p8
Short name=Trp-p8
Gene names
Name:TRPM8
Synonyms:LTRPC6, TRPP8
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1104 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel. Ref.2 Ref.3 Ref.8

Subunit structure

Homotetramer By similarity. Isoform 2 and isoform 3 interact with the C-terminus of isoform 1 in a thermosensitive manner with decreased interaction at 21 degrees Celsius compared to 37 degrees Celsius. Ref.3

Subcellular location

Cell membrane; Multi-pass membrane protein. Membrane raft. Endoplasmic reticulum membrane. Note: Localizes to membrane rafts but is also located in the cell membrane outside of these regions where channel response to cold is enhanced compared to membrane rafts By similarity. Located in the endoplasmic reticulum in prostate cancer cells. Ref.2 Ref.3

Tissue specificity

Expressed in prostate. Also expressed in prostate tumors and in non-prostatic primary tumors such as colon, lung, breast and skin tumors. Ref.1 Ref.2 Ref.3 Ref.7

Domain

The coiled coil region is required for multimerization. Ref.9

Miscellaneous

The sensation of coolness triggered by eucalyptol or menthol may be explained by the fact that menthol and cool temperatures sensations are detected by this protein.

Its expression in most prostate tumors as well as the presence of an immunogenic epitope suggest that it may be suitable for the design of peptide vaccination strategies for prostate cancers.

Sequence similarities

Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM8 sub-subfamily. [View classification]

Caution

The 192-residue sequence submitted as AAS45276 has been confirmed by the authors of Ref.3 to be incorrect as translation starts from a downstream methionine.

Sequence caution

The sequence AAH01135.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

The sequence AAS45276.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
   Biological processIon transport
Sensory transduction
Transport
   Cellular componentCell membrane
Endoplasmic reticulum
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainCoiled coil
Transmembrane
Transmembrane helix
   Molecular functionIon channel
   PTMGlycoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcalcium ion transmembrane transport

Traceable author statement. Source: Reactome

cellular calcium ion homeostasis

Inferred from electronic annotation. Source: Ensembl

ion transmembrane transport

Traceable author statement. Source: Reactome

protein homotetramerization

Inferred from electronic annotation. Source: Ensembl

protein homotrimerization

Inferred from electronic annotation. Source: Ensembl

response to cold

Inferred from electronic annotation. Source: Ensembl

thermoception

Inferred from electronic annotation. Source: Ensembl

transmembrane transport

Traceable author statement. Source: Reactome

   Cellular_componentendoplasmic reticulum membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

external side of plasma membrane

Inferred from electronic annotation. Source: Ensembl

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

membrane raft

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functioncalcium channel activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q7Z2W7-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q7Z2W7-2)

Also known as: sTRPM8-18; sM8-18;

The sequence of this isoform differs from the canonical sequence as follows:
     1-188: Missing.
     234-242: GYFLAQYLM → VPVGQEEVC
     243-1104: Missing.
Isoform 3 (identifier: Q7Z2W7-3)

Also known as: sTRPM8-6; sM8-6;

The sequence of this isoform differs from the canonical sequence as follows:
     1-77: Missing.
     234-242: GYFLAQYLM → VPVGQEEVC
     243-1104: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 11041104Transient receptor potential cation channel subfamily M member 8
PRO_0000215333

Regions

Topological domain1 – 691691Cytoplasmic Potential
Transmembrane692 – 71221Helical; Name=1; Potential
Topological domain713 – 73422Extracellular Potential
Transmembrane735 – 75521Helical; Name=2; Potential
Topological domain756 – 7594Cytoplasmic Potential
Transmembrane760 – 78021Helical; Name=3; Potential
Topological domain781 – 79414Extracellular Potential
Transmembrane795 – 81521Helical; Name=4; Potential
Topological domain816 – 82914Cytoplasmic Potential
Transmembrane830 – 85021Helical; Name=5; Potential
Topological domain851 – 958108Extracellular Potential
Transmembrane959 – 97921Helical; Name=6; Potential
Topological domain980 – 1104125Cytoplasmic Potential
Region187 – 1959Epitope; activates specific cytotoxic T lymphocytes
Coiled coil1071 – 110434 Potential

Amino acid modifications

Glycosylation9341N-linked (GlcNAc...) (complex) Ref.9

Natural variations

Alternative sequence1 – 188188Missing in isoform 2.
VSP_053268
Alternative sequence1 – 7777Missing in isoform 3.
VSP_012330
Alternative sequence234 – 2429GYFLAQYLM → VPVGQEEVC in isoform 2 and isoform 3.
VSP_012332
Alternative sequence243 – 1104862Missing in isoform 2 and isoform 3.
VSP_012333
Natural variant2471R → T.
Corresponds to variant rs13004520 [ dbSNP | Ensembl ].
VAR_052383
Natural variant2511Y → C.
Corresponds to variant rs17868387 [ dbSNP | Ensembl ].
VAR_052384
Natural variant4191S → N.
Corresponds to variant rs7593557 [ dbSNP | Ensembl ].
VAR_059837
Natural variant4621M → T.
Corresponds to variant rs28902173 [ dbSNP | Ensembl ].
VAR_052385
Natural variant7321T → I.
Corresponds to variant rs17862932 [ dbSNP | Ensembl ].
VAR_052386
Natural variant8211N → S.
Corresponds to variant rs28902201 [ dbSNP | Ensembl ].
VAR_052387

Experimental info

Mutagenesis8211N → Q: No effect on glycosylation or ability to form functional channels. Ref.9
Mutagenesis9341N → Q: Abolishes glycosylation. Ref.9
Mutagenesis9461H → N: No effect on glycosylation or channel activity. Ref.9
Mutagenesis10891L → P: Abolishes multimerization and channel activity. Reduces cell surface expression. Ref.9
Sequence conflict581T → I in AAM10446. Ref.1
Sequence conflict6931W → R in BAB86335. Ref.6
Sequence conflict7951T → A in AAP92167. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified April 3, 2007. Version 2.
Checksum: 5D88F5081EDFA632

FASTA1,104127,685
        10         20         30         40         50         60 
MSFRAARLSM RNRRNDTLDS TRTLYSSASR STDLSYSESD LVNFIQANFK KRECVFFTKD 

        70         80         90        100        110        120 
SKATENVCKC GYAQSQHMEG TQINQSEKWN YKKHTKEFPT DAFGDIQFET LGKKGKYIRL 

       130        140        150        160        170        180 
SCDTDAEILY ELLTQHWHLK TPNLVISVTG GAKNFALKPR MRKIFSRLIY IAQSKGAWIL 

       190        200        210        220        230        240 
TGGTHYGLMK YIGEVVRDNT ISRSSEENIV AIGIAAWGMV SNRDTLIRNC DAEGYFLAQY 

       250        260        270        280        290        300 
LMDDFTRDPL YILDNNHTHL LLVDNGCHGH PTVEAKLRNQ LEKYISERTI QDSNYGGKIP 

       310        320        330        340        350        360 
IVCFAQGGGK ETLKAINTSI KNKIPCVVVE GSGQIADVIA SLVEVEDALT SSAVKEKLVR 

       370        380        390        400        410        420 
FLPRTVSRLP EEETESWIKW LKEILECSHL LTVIKMEEAG DEIVSNAISY ALYKAFSTSE 

       430        440        450        460        470        480 
QDKDNWNGQL KLLLEWNQLD LANDEIFTND RRWESADLQE VMFTALIKDR PKFVRLFLEN 

       490        500        510        520        530        540 
GLNLRKFLTH DVLTELFSNH FSTLVYRNLQ IAKNSYNDAL LTFVWKLVAN FRRGFRKEDR 

       550        560        570        580        590        600 
NGRDEMDIEL HDVSPITRHP LQALFIWAIL QNKKELSKVI WEQTRGCTLA ALGASKLLKT 

       610        620        630        640        650        660 
LAKVKNDINA AGESEELANE YETRAVELFT ECYSSDEDLA EQLLVYSCEA WGGSNCLELA 

       670        680        690        700        710        720 
VEATDQHFIA QPGVQNFLSK QWYGEISRDT KNWKIILCLF IIPLVGCGFV SFRKKPVDKH 

       730        740        750        760        770        780 
KKLLWYYVAF FTSPFVVFSW NVVFYIAFLL LFAYVLLMDF HSVPHPPELV LYSLVFVLFC 

       790        800        810        820        830        840 
DEVRQWYVNG VNYFTDLWNV MDTLGLFYFI AGIVFRLHSS NKSSLYSGRV IFCLDYIIFT 

       850        860        870        880        890        900 
LRLIHIFTVS RNLGPKIIML QRMLIDVFFF LFLFAVWMVA FGVARQGILR QNEQRWRWIF 

       910        920        930        940        950        960 
RSVIYEPYLA MFGQVPSDVD GTTYDFAHCT FTGNESKPLC VELDEHNLPR FPEWITIPLV 

       970        980        990       1000       1010       1020 
CIYMLSTNIL LVNLLVAMFG YTVGTVQENN DQVWKFQRYF LVQEYCSRLN IPFPFIVFAY 

      1030       1040       1050       1060       1070       1080 
FYMVVKKCFK CCCKEKNMES SVCCFKNEDN ETLAWEGVMK ENYLVKINTK ANDTSEEMRH 

      1090       1100 
RFRQLDTKLN DLKGLLKEIA NKIK 

« Hide

Isoform 2 (sTRPM8-18) (sM8-18) [UniParc].

Checksum: 5DB74DAF67EBDCED
Show »

FASTA545,940
Isoform 3 (sTRPM8-6) (sM8-6) [UniParc].

Checksum: 1EC4CEA05A33B6B6
Show »

FASTA16518,655

References

« Hide 'large scale' references
[1]"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."
Tsavaler L., Shapero M.H., Morkowski S., Laus R.
Cancer Res. 61:3760-3769(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
Tissue: Prostate.
[2]"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. 280:39423-39435(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Prostate and Prostate cancer.
[3]"Regulation of activity of transient receptor potential melastatin 8 (TRPM8) channel by its short isoforms."
Bidaux G., Beck B., Zholos A., Gordienko D., Lemonnier L., Flourakis M., Roudbaraki M., Borowiec A.S., Fernandez J., Delcourt P., Lepage G., Shuba Y., Skryma R., Prevarskaya N.
J. Biol. Chem. 287:2948-2962(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Prostate cancer.
[4]Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Skin.
[6]"Molecular cloning of a novel member of LTRP channel family, LTRPC6."
Sano Y., Inamura K., Miyake A., Mochizuki S., Yokoi H., Kitada C., Nozawa K., Matsushime H., Furuichi K.
Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 10-1104 (ISOFORM 1).
[7]"Identification of an HLA-A*0201-restricted T-cell epitope derived from the prostate cancer-associated protein trp-p8."
Kiessling A., Fuessel S., Schmitz M., Stevanovic S., Meye A., Weigle B., Klenk U., Wirth M.P., Rieber E.P.
Prostate 56:270-279(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, EPITOPE MAPPING.
[8]"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 430:748-754(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Trafficking and assembly of the cold-sensitive TRPM8 channel."
Erler I., Al-Ansary D.M., Wissenbach U., Wagner T.F., Flockerzi V., Niemeyer B.A.
J. Biol. Chem. 281:38396-38404(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT ASN-934, MUTAGENESIS OF ASN-821; ASN-934; HIS-946 AND LEU-1089, ROLE OF COILED COIL DOMAIN.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY090109 mRNA. Translation: AAM10446.1.
AY328400 mRNA. Translation: AAP92167.1.
DQ139309 mRNA. Translation: AAZ73614.1.
AY532375 mRNA. Translation: AAS45275.1.
AY532376 mRNA. Translation: AAS45276.1. Different initiation.
CH471063 Genomic DNA. Translation: EAW71068.1.
BC001135 mRNA. Translation: AAH01135.1. Different initiation.
AB061779 mRNA. Translation: BAB86335.1.
RefSeqNP_076985.4. NM_024080.4.
UniGeneHs.366053.

3D structure databases

ProteinModelPortalQ7Z2W7.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid122512. 6 interactions.
STRING9606.ENSP00000323926.

Chemistry

BindingDBQ7Z2W7.
ChEMBLCHEMBL1075319.
DrugBankDB00825. Menthol.
GuidetoPHARMACOLOGY500.

Protein family/group databases

TCDB1.A.4.5.7. the transient receptor potential ca(2+) channel (trp-cc) family.

PTM databases

PhosphoSiteQ7Z2W7.

Polymorphism databases

DMDM143811469.

Proteomic databases

PaxDbQ7Z2W7.
PRIDEQ7Z2W7.

Protocols and materials databases

DNASU79054.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000324695; ENSP00000323926; ENSG00000144481. [Q7Z2W7-1]
ENST00000355722; ENSP00000347956; ENSG00000144481.
ENST00000409625; ENSP00000386771; ENSG00000144481. [Q7Z2W7-3]
GeneID79054.
KEGGhsa:79054.
UCSCuc002vvh.3. human. [Q7Z2W7-1]
uc002vvi.3. human. [Q7Z2W7-2]
uc002vvj.3. human. [Q7Z2W7-3]

Organism-specific databases

CTD79054.
GeneCardsGC02P234842.
HGNCHGNC:17961. TRPM8.
HPAHPA024117.
HPA029542.
MIM606678. gene.
neXtProtNX_Q7Z2W7.
PharmGKBPA38270.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG253824.
HOGENOMHOG000236350.
HOVERGENHBG100888.
InParanoidQ7Z2W7.
KOK04983.
OMADFAHCTF.
OrthoDBEOG725DH1.
PhylomeDBQ7Z2W7.
TreeFamTF314204.

Enzyme and pathway databases

ReactomeREACT_15518. Transmembrane transport of small molecules.

Gene expression databases

ArrayExpressQ7Z2W7.
BgeeQ7Z2W7.
CleanExHS_TRPM8.
GenevestigatorQ7Z2W7.

Family and domain databases

InterProIPR005821. Ion_trans_dom.
[Graphical view]
PfamPF00520. Ion_trans. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiTRPM8.
GenomeRNAi79054.
NextBio67809.
PROQ7Z2W7.
SOURCESearch...

Entry information

Entry nameTRPM8_HUMAN
AccessionPrimary (citable) accession number: Q7Z2W7
Secondary accession number(s): Q3YFM7 expand/collapse secondary AC list , Q6QNH9, Q8TAC3, Q8TDX8, Q9BVK1
Entry history
Integrated into UniProtKB/Swiss-Prot: December 21, 2004
Last sequence update: April 3, 2007
Last modified: April 16, 2014
This is version 99 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM