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.

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).

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).

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).

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).

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).