TRPM8 (transient receptor potential cation channel, subfamily M, member 8)

2013-05-01   María Llanos Valero , Luis A Pardo 

Molecular Oncology Laboratory. Facultad de Medicina. CRIB. UCLM. Albacete, Spain (MLV); Department of Molecular Biology of Neuronal Signals, Max-Planck Institute of Experimental Medicine, Gottingen, Germany (LAP)

Identity

HGNC
LOCATION
2q37.1
LOCUSID
ALIAS
LTRPC6,LTrpC-6,TRPP8,trp-p8
FUSION GENES

DNA/RNA

Atlas Image
Genomic structure of human TRPM8.

Description

TRPM8 consists of 27 exons that span102 kilo base pairs located at 2q37. The open reading frame (ORF) has 3312 bp resulting in an 1104 residue product. It exhibits the highly conserved region characteristic of the TRP family. The ion pore domains are located between exons 16 and 20.

Transcription

The 1104 aa compose a each of the 130 KDa subunits that convey to form a homotetramer. Alternative splicing produces 11 mRNA species. The promoter contains some transcription factor binding sites for NKX3-1, NKX2-5, USF1, MYC, LMOR and ARNt (Kaiser, 2004). There are two short functional splice variants described in prostate cancer; SM8α and SM8β, that act as regulatory subunits of the full-length protein (Bidaux et al., 2012).

Proteins

Atlas Image
Schematic representation of TRPM8 protein (adapted from Latorre et al., 2011).

Description

Structurally, the TRPM8 channel is formed by four identical subunits. Each subunit shows 6 transmembrane domains (S1-S6) that surround the central pore, with S5 and S6 forming the gate and selective filter. The N- and C-terminal domains are in the cytoplasmic side (Peier et al., 2002; Latorre et al., 2011). The C- terminal domain is essential for the maturation, oligomerization and trafficking of the channel to the plasma membrane (Erler et al., 2006; Cayouette and Boulay, 2007). The "TRP box", in common with all the TRP family members and a binding site for PIP2, are located in this C-terminal tail. Functional TRPM8 channels require the presence of the COOH terminal as well as the region compromised between amino acids 40 to 86 of the NH2 terminal (Phelps and Gaudet, 2007). The protein shows 8 putative glycosylation sites and an immunogenic epitope that will facilitate the future design of peptide vaccination (Kiessling et al., 2003).

Expression

TRPM8 is expressed mainly in a subpopulation of primary afferent neurons from both, dorsal root and trigeminal ganglia, and in the nodose and geniculate ganglia in the peripheral nervous system. The protein has been also identified in prostate and genitourinary tract, bladder, sperm, vascular smooth muscle, liver, lung and odontoblasts (Latorre et al., 2011).

Localisation

The channel is expressed in the plasma membrane and in the membrane rafts. In prostate cancer cells, it is expressed in the endoplasmic reticulum membrane too (Latorre et al., 2011).

Function

TRPM8 is a non-selective cation channel that primarily mediates the detection of cold thermal stimuli by primary afferent sensory neurons of afferent nerve fibres. In these cells, a temperature decrease from 28 to 8°C generates an increase in the intracellular calcium and action potential firing (McKemy et al., 2002; Peier et al., 2002; Bautista et al., 2007). This cold sensitivity is strongly compromised in the knock-out mice, disclosing a central role for TRPM8 in the detection of innocuous cold in vivo (Knowlton et al., 2013).
TRPM8 is a polymodal receptor, activated by cold and also by membrane depolarization, as well as several inflammatory agents, and natural and chemical compounds as menthol and icilin. The activation by icilin requiries the presence of intracellular calcium (Chuang et al., 2004).
The residues involved in menthol activation are Tyr745 in the S2 segment and Tyr1005 and Leu1009, located in the C-terminus (Bandell et al., 2006).
Besides menthol and icilin, there are many agonist described for the channel as WS-12, CPS-39, linalool, geraniol, frescolat etc, as well as well-known antagonists; BCTC, thio-BCTC, capsazepine, AMTB and JNJ41876666 (Behrendt et al., 2004; Valero et al., 2012; Journigan and Zaveri, 2013).
One year before being cloned, TRPM8 was described as a transcript overexpressed in prostate cancer cells (Tsavaler et al., 2001; Zhang and Barritt, 2004). Nowadays, the presence of the channel has been described for a variety of tumours (Lehenkyi and Prevarskaya, 2011) as melanoma (Guo et al., 2012), colon or breast (Dhennin-Duthille et al., 2011).

Modulation
TRPM8 channels are activated by stimulation of tyrosin-kinase and protein G-coupled receptors. The channel is also capable of activating Gq protein (Klasen et al., 2012).
PI(4,5)P2 acts as a positive modulator of cold and menthol sensitivity by changing the voltage-sensitivity of the channel (Rohacs et al., 2005; Daniels et al., 2009; Yudin and Rohacs, 2012).
Protein Kinase C is implicated in TRPM8 desensitization (Yudin and Rohacs, 2012).
Phospolipase C (PLC)-coupled receptors mediate adaptation of TRPM8 to thermal stimuli (Daniels et al., 2009; Yudin and Rohacs, 2012).
There are indications of modulation by PKC and PKA, which would underlie reduced responses to cold and menthol in neurons in the presence of bradykinin and prostaglandin E2 (Latorre et al., 2011; Yudin and Rohacs, 2012).
TRPM8 also co-expresses with TrkA, the high affinity tyrosine kinase receptor for NGF (Latorre et al., 2011).

Implicated in

Entity name
Prostate cancer
Note
The TRPM8 channel is expressed in prostate cancer and normal prostatic cells. In the prostate cancer cells, the channel is functional in the cells of the different stadia of the illness. Inhibition of the expression or function of the channel reduces proliferation rates and proliferative fraction in the tumor cells, but not in non-tumor prostate cells. There is no consistent acceleration of growth after stimulation of the channel with menthol or icilin, indicating that basal TRPM8 expression is enough to sustain growth of prostate cancer cells. The evidence supports a tumor-specific role of TRPM8 rather than a tumor-specific expression of the channel, thus reinforcing the relevance of this channel as a candidate for prostate cancer therapy (Zhang and Barritt, 2004; Van Haute et al., 2010; Valero et al., 2012).
Entity name
Melanoma
Note
TRPM8 channels are expressed in human melanocytes and melanoma cells where its activation produces sustained Ca2+ influx. Different studies have revealed the involvement of the channel in inhibition of pigmentation and melanoma proliferation. Targeting TRPM8 with natural compounds as adjuvant may help in melanoma therapy (Guo et al., 2012).
Entity name
Pain
Note
The hypersensitivity to cold manifested as cold hyperalgesia or allodynia, often noted in patients with neuropathic pain, is mediated by TRPM8, making the channel a potential molecular target for pain relief. There are however concerns regarding thermoregulation upon manipulation of TRPM8 activity (Belmonte et al., 2009; Caspani et al., 2009; Brederson et al., 2013).

Bibliography

Pubmed IDLast YearTitleAuthors
165207352006High-throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol.Bandell M et al
175386222007The menthol receptor TRPM8 is the principal detector of environmental cold.Bautista DM et al
147577002004Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay.Behrendt HJ et al
193994842009Converting cold into pain.Belmonte C et al
221281732012Regulation of activity of transient receptor potential melastatin 8 (TRPM8) channel by its short isoforms.Bidaux G et al
235001952013Targeting TRP channels for pain relief.Brederson JD et al
198126882009The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain.Caspani O et al
173687562007Intracellular trafficking of TRP channels.Cayouette S et al
153633962004The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel.Chuang HH et al
190198302009Activity of the neuronal cold sensor TRPM8 is regulated by phospholipase C via the phospholipid phosphoinositol 4,5-bisphosphate.Daniels RL et al
221789342011High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.Dhennin-Duthille I et al
170651482006Trafficking and assembly of the cold-sensitive TRPM8 channel.Erler I et al
228975722012Role of TRPM in melanocytes and melanoma.Guo H et al
231596432013TRPM8 ion channel ligands for new therapeutic applications and as probes to study menthol pharmacology.Journigan VB et al
128583552003Identification of an HLA-A*0201-restricted T-cell epitope derived from the prostate cancer-associated protein trp-p8.Kiessling A et al
224607252012The TRPM8 ion channel comprises direct Gq protein-activating capacity.Klasen K et al
234079432013A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia.Knowlton WM et al
218410752011A cool channel in cold transduction.Latorre R et al
212903342011Oncogenic TRP channels.Lehen'kyi V et al
118828882002Identification of a cold receptor reveals a general role for TRP channels in thermosensation.McKemy DD et al
118933402002A TRP channel that senses cold stimuli and menthol.Peier AM et al
179086852007The role of the N terminus and transmembrane domain of TRPM8 in channel localization and tetramerization.Phelps CB et al
158520092005PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.Rohács T et al
113258492001Trp-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 et al
232516352012TRPM8 ion channels differentially modulate proliferation and cell cycle distribution of normal and cancer prostate cells.Valero ML et al
207303792010TRP channels in human prostate.Van Haute C et al
220616192012Regulation of TRPM8 channel activity.Yudin Y et al
155487062004Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.Zhang L et al

Other Information

Locus ID:

NCBI: 79054
MIM: 606678
HGNC: 17961
Ensembl: ENSG00000144481

Variants:

dbSNP: 79054
ClinVar: 79054
TCGA: ENSG00000144481
COSMIC: TRPM8

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000144481ENST00000324695Q7Z2W7
ENSG00000144481ENST00000324695W8DTH1
ENSG00000144481ENST00000355722A0A0C4DFT0
ENSG00000144481ENST00000409625Q7Z2W7
ENSG00000144481ENST00000409625A0A1L1Z822
ENSG00000144481ENST00000433712A0A0A0MSV2
ENSG00000144481ENST00000439148H7BZP4
ENSG00000144481ENST00000444298F8WD55
ENSG00000144481ENST00000456930H0Y7P0

Expression (GTEx)

0
5
10
15

Pathways

PathwaySourceExternal ID
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Ion channel transportREACTOMER-HSA-983712
Stimuli-sensing channelsREACTOMER-HSA-2672351
TRP channelsREACTOMER-HSA-3295583

References

Pubmed IDYearTitleCitations
153068012004The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels.315
154922282004Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8.123
180942542007Diversity in the neural circuitry of cold sensing revealed by genetic axonal labeling of transient receptor potential melastatin 8 neurons.91
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
175214362007Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy.68
161747752005Novel 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.59
194043982009Inorganic polyphosphate modulates TRPM8 channels.56
175107042007Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function.51
191594522009Pore dilation occurs in TRPA1 but not in TRPM8 channels.44
193631312009Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone.44

Citation

María Llanos Valero ; Luis A Pardo

TRPM8 (transient receptor potential cation channel, subfamily M, member 8)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version: http://atlasgeneticsoncology.org/gene/42709/trpm8