Q7Z2W7 (TRPM8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1104 AA.
Sequence status	Complete.
Protein existence	Evidence 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 agonists 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. Ref.2 Ref.8
Subunit structure	Homotetramer By similarity.
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
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.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]

Ontologies

Keywords
Biological process	Ion transport Sensory transduction Transport
Cellular component	Cell membrane Endoplasmic reticulum Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Coiled coil Transmembrane Transmembrane helix
Molecular function	Ion channel
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	response to cold Inferred from electronic annotation. Source: Compara
Cellular_component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW membrane raft Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ion channel activity Inferred from electronic annotation. Source: Compara
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: Beta;

The sequence of this isoform differs from the canonical sequence as follows:
     1-64: MSFRAARLSM...VFFTKDSKAT → MKSFLPVHTIVLIR
     234-242: GYFLAQYLM → VPVGQEEVC
     243-1104: Missing.

Isoform 3 (identifier: Q7Z2W7-3)

Also known as: Alpha;

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1104	1104	Transient receptor potential cation channel subfamily M member 8		PRO_0000215333
Regions
	Topological domain	1 – 691	691	Cytoplasmic Potential
	Transmembrane	692 – 712	21	Helical; Name=1; Potential
	Topological domain	713 – 734	22	Extracellular Potential
	Transmembrane	735 – 755	21	Helical; Name=2; Potential
	Topological domain	756 – 759	4	Cytoplasmic Potential
	Transmembrane	760 – 780	21	Helical; Name=3; Potential
	Topological domain	781 – 794	14	Extracellular Potential
	Transmembrane	795 – 815	21	Helical; Name=4; Potential
	Topological domain	816 – 829	14	Cytoplasmic Potential
	Transmembrane	830 – 850	21	Helical; Name=5; Potential
	Topological domain	851 – 958	108	Extracellular Potential
	Transmembrane	959 – 979	21	Helical; Name=6; Potential
	Topological domain	980 – 1104	125	Cytoplasmic Potential
	Region	187 – 195	9	Epitope; activates specific cytotoxic T lymphocytes
	Coiled coil	1071 – 1104	34	Potential
Amino acid modifications
	Glycosylation	934	1	N-linked (GlcNAc...) (complex) Ref.9
Natural variations
	Alternative sequence	1 – 77	77	Missing in isoform 3.		VSP_012330
	Alternative sequence	1 – 64	64	MSFRA…DSKAT → MKSFLPVHTIVLIR in isoform 2.		VSP_012331
	Alternative sequence	234 – 242	9	GYFLAQYLM → VPVGQEEVC in isoform 2 and isoform 3.		VSP_012332
	Alternative sequence	243 – 1104	862	Missing in isoform 2 and isoform 3.		VSP_012333
	Natural variant	247	1	R → T. Corresponds to variant rs13004520 [ dbSNP | Ensembl ].		VAR_052383
	Natural variant	251	1	Y → C. Corresponds to variant rs17868387 [ dbSNP | Ensembl ].		VAR_052384
	Natural variant	419	1	S → N. Corresponds to variant rs7593557 [ dbSNP | Ensembl ].		VAR_059837
	Natural variant	462	1	M → T. Corresponds to variant rs28902173 [ dbSNP | Ensembl ].		VAR_052385
	Natural variant	732	1	T → I. Corresponds to variant rs17862932 [ dbSNP | Ensembl ].		VAR_052386
	Natural variant	821	1	N → S. Corresponds to variant rs28902201 [ dbSNP | Ensembl ].		VAR_052387
Experimental info
	Mutagenesis	821	1	N → Q: No effect on glycosylation or ability to form functional channels. Ref.9
	Mutagenesis	934	1	N → Q: Abolishes glycosylation. Ref.9
	Mutagenesis	946	1	H → N: No effect on glycosylation or channel activity. Ref.9
	Mutagenesis	1089	1	L → P: Abolishes multimerization and channel activity. Reduces cell surface expression. Ref.9
	Sequence conflict	58	1	T → I in AAM10446. Ref.1
	Sequence conflict	693	1	W → R in BAB86335. Ref.6
	Sequence conflict	795	1	T → A in AAP92167. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified April 3, 2007. Version 2. Checksum: 5D88F5081EDFA632	FASTA	1,104	127,685
	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
	Isoform 2 (Beta) [UniParc]. Checksum: 497E80248CF1D45C	FASTA	192	21,740
	10 20 30 40 50 60 MKSFLPVHTI VLIRENVCKC GYAQSQHMEG TQINQSEKWN YKKHTKEFPT DAFGDIQFET 70 80 90 100 110 120 LGKKGKYIRL SCDTDAEILY ELLTQHWHLK TPNLVISVTG GAKNFALKPR MRKIFSRLIY 130 140 150 160 170 180 IAQSKGAWIL TGGTHYGLMK YIGEVVRDNT ISRSSEENIV AIGIAAWGMV SNRDTLIRNC 190 DAEVPVGQEE VC
	Isoform 3 (Alpha) [UniParc]. Checksum: 1EC4CEA05A33B6B6	FASTA	165	18,655
	10 20 30 40 50 60 MEGTQINQSE KWNYKKHTKE FPTDAFGDIQ FETLGKKGKY IRLSCDTDAE ILYELLTQHW 70 80 90 100 110 120 HLKTPNLVIS VTGGAKNFAL KPRMRKIFSR LIYIAQSKGA WILTGGTHYG LMKYIGEVVR 130 140 150 160 DNTISRSSEE NIVAIGIAAW GMVSNRDTLI RNCDAEVPVG QEEVC

References

	« Hide 'large scale' referencesShow '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]	"Characterization of short TRPM8 splice beta from prostate cancer cell line LNCaP." Bidaux G., Roudbaraki M., Gauthier J., Prevarskaya N. Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
[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. , 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. CH471063 Genomic DNA. Translation: EAW71068.1. BC001135 mRNA. Translation: AAH01135.1. AB061779 mRNA. Translation: BAB86335.1.
IPI	IPI00031662. IPI00152033. IPI00515002.
RefSeq	NP_076985.4. NM_024080.4.
UniGene	Hs.366053.
3D structure databases
ProteinModelPortal	Q7Z2W7.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000323926.
Protein family/group databases
TCDB	1.A.4.5.7. transient receptor potential Ca2+ channel (TRP-CC) family.
PTM databases
PhosphoSite	Q7Z2W7.
Polymorphism databases
DMDM	143811469.
Proteomic databases
PaxDb	Q7Z2W7.
PRIDE	Q7Z2W7.
Protocols and materials databases
DNASU	79054.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000324695; ENSP00000323926; ENSG00000144481. ENST00000355722; ENSP00000347956; ENSG00000144481. ENST00000409625; ENSP00000386771; ENSG00000144481.
GeneID	79054.
KEGG	hsa:79054.
UCSC	uc002vvh.3. human. uc002vvi.3. human. uc002vvj.3. human.
Organism-specific databases
CTD	79054.
GeneCards	GC02P234842.
HGNC	HGNC:17961. TRPM8.
HPA	HPA024117. HPA029542.
MIM	606678. gene.
neXtProt	NX_Q7Z2W7.
PharmGKB	PA38270.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG253824.
HOGENOM	HOG000236350.
HOVERGEN	HBG100888.
InParanoid	Q7Z2W7.
KO	K04983.
OMA	DFAHCTF.
OrthoDB	EOG4SJ5D0.
PhylomeDB	Q7Z2W7.
Gene expression databases
ArrayExpress	Q7Z2W7.
Bgee	Q7Z2W7.
CleanEx	HS_TRPM8.
Genevestigator	Q7Z2W7.
GermOnline	ENSG00000144481. Homo sapiens.
Family and domain databases
InterPro	IPR005821. Ion_trans_dom. [Graphical view]
Pfam	PF00520. Ion_trans. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	Q7Z2W7.
ChEMBL	CHEMBL1075319.
DrugBank	DB00825. Menthol.
GenomeRNAi	79054.
NextBio	67809.
SOURCE	Search...

Entry information

Entry name

TRPM8_HUMAN

Accession

Primary (citable) accession number: Q7Z2W7
Secondary accession number(s): Q3YFM7 , Q6QNH9, Q8TAC3, Q8TDX8, Q9BVK1

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 21, 2004
Last sequence update:	April 3, 2007
Last modified:	May 1, 2013
This is version 89 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.