The three members of the TRPML sub-family are not well characterized. TRPML1 is known to be localized in late endosomes. This subunit also contains a lipase domain between its S1 and S2 segments. While the function of this domain is unknown it has been proposed that it is involved in channel regulation. Physiological studies have described TRPML1 channels as proton leak channels in lysosomes responsible for preventing these organelles from becoming too acidic. TRPML2 and TRPML3 have yet to be characterized.[1]

Deficiencies can lead to enlarged vacuoles.

Three independent research groups have reported that mice lacking TRPM8 gene are severely impaired in their ability to detect cold temperatures.[4] Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli. Many research groups, both in universities and pharmaceutical companies, are now actively involved in looking for selective TRPM8 ligands to be used as new generation of neuropathic analgesic drugs. Interestingly, low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions,[5] whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers.[6]

TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain.[7] Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models.[8]

TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes.[9] Furthermore, TRPM8 is upregulated in many prostate cancer cell lines and Dendreon/Genentech are pursuing an agonist approach to induce apoptosis and prostate cancer cell death.

The TRPM8 protein is expresed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as menthol and icilin where as WS-12 and CPS-369 are the most selective agonist of TRPM8.

TRPs, mammalian homologs of the Drosophila transient receptor potential (trp) protein, are ion channels that are thought to mediate capacitative calcium entry into the cell. TRP-PLIK is a protein that is both an ion channel and a kinase. As a channel, it conducts calcium and monovalent cations to depolarize cells and increase intracellular calcium. As a kinase, it is capable of phosphorylating itself and other substrates. The kinase activity is necessary for channel function, as shown by its dependence on intracellular ATP and by the kinase mutants.[supplied by OMIM]

The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been identified.[1] TRPM3 was shown to be activated by the neurosteroid pregnenolone sulphate in hepatocytes. The activation causes calcium influx and subsequent insulin release, therefore it is suggested that TRPM3 modulates glucose homeostasis.

The protein encoded by this gene is a calcium-permeable cation channel that is regulated by free intracellular ADP-ribose. The encoded protein is activated by oxidative stress and confers susceptibility to cell death. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.

TRPC6 is a transient receptor potential ion channel associated with focal segmental glomerulosclerosis.

The protein encoded by this gene is similar to the transient receptor potential (Trp) calcium channel family members. The expression of this protein is inversely correlated with melanoma aggressiveness, suggesting that it suppresses melanoma metastasis[1]. The expression of the TRPM1 gene is regulated by the Microphthalmia-associated transcription factor

The mechanism of activation also varies greatly among TRPM channels.
TRPM2 is activated by ADP-ribose Adenosine 5′-diphosphoribose and functions as a sensor of redox status in cells.[3]
TRPM4/5 are activated by intracellular calcium.
TRPM8, conversely, can be activated by low temperatures, menthol, eucalyptol and icilin.

Unlike the TRPC and TRPV sub-families, TRPM subunits do not contain N-terminal ankyrin repeat motifs but, rather, contain entire functional proteins in their C-termini. TRPM6 and TRPM7, for example, contain functional ?-kinase segments, which are a type of serine/threonine-specific protein kinase.