TRPM4

TRPM4 is the acronym for "Transient receptor potential cation channel, subfamily M, member 4", a Ca(2+)-activated non-selective ion channel. The gene of the same name encoding this ion channel is located on chromosome 19q13.33. 2 gene products are known: TRPM4a and the shorter TRPM4b (Launay et al. 2002). The ion channel is activated by an increase in intracellular Ca(2+) and is regulated by several factors such as temperature.TRPM4 allows Na (+) to enter the cell when activated, but is completely impermeable to Ca (2+). Unlike TRPM5, its closest relative in the transient receptor potential family, TRPM4 proteins are widely expressed in the body (Mathar I et al. 2014)

TRP channels are phylogenetically early signaling pathways (they can already be detected in yeast cells). The first TRP channel was identified in 1989 in connection with visual perception in Drosophila melanogaster. In a Drosophila mutant (trp343), it was shown that its photoreceptors responded to light stimuli only with a transient, i.e. rapidly inactivating, membrane current. In the non-mutated wild type, however, the current flow persisted as long as light hit the photoreceptor. The mutant protein -TRP- was cloned in 1989. Thus, the name "transient receptor potential" - TRP- refers to the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster. TRP channels exert important functions in primary signaling pathways for the regulated influx of Ca2+ into a cell in both vertebrates and non-vertebrates. TRP channels in humans play an important role in the sensation of different types of taste (sweet, bitter, umami) as well as in the perception of pain, heat, warmth or cold, pressure and light. It is believed that some TRP channels in the body behave like microscopic thermosensors. To date, 28 TRP channel genes have been identified in mammals (Nilius B et al. 2011).

TRPMs(except for TRPM4 and TRMP5) are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N- and C-termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain. TRPM3, unlike other TRPM channels, is activated by sphingosine (Farooqi et al. 2011). Its activation triggers a signal transduction cascade of mitogen-activated kinases and stimulus-response transcription factors.

TRPM4 is a mediator of pressure-induced membrane depolarization and arterial constriction (review by Farooqi et al. 2011). The highest TRPM4 expression was found in heart (here preferentially in Purkinje fibers), prostate and colon. In the fetus, the highest TRPM4 expression was found in the kidney.

The skin also abundantly expresses TRP channels of different subtypes, which play an essential role in maintaining skin functionality (Wang H et al. 2019). Wang et al. (2019) detected TRPM4 mRNA in epidermis from normal dorsal foot skin and in the human epidermal keratinocyte cell line HaCaT.

Mutations in the TRPM4 gene, which encodes a Ca2+-activated monovalent cation channel of the same name, are detected in 2 syndromes:

• Autosomal dominant progressive symmetric erythrokeratoderma (Wang et al. 2019)

and

• autosomal recessive Brugada type 1 syndrome (Janin A et al. 2019).

Stallmeyer et al (2012) analyzed the TRPM4 gene in 160 unrelated patients with different types of inherited cardiac arrhythmias and identified 8 missense mutations in 8 patients.

In three separate families with progressive symmetric erythrokeratoderma, Wang et al (2019) identified 2 missense mutations (c.3099C>G and c.3119T>C), both located in the S6 transmembrane domain of the TRPM4 protein. Electrophysiological studies on the mutants revealed considerable hyperactivity as evidenced by marked baseline activity, increased sensitivity to intracellular Ca2+, and increased resting membrane potential. In vitro, there was increased proliferation in keratinocytes. It can be suggested that TRPM4 is an important player in the pathogenesis of TRP channelopathies of the skin. TRPM4 may represent a potential target for the treatment of hyperkeratotic skin diseases.

TRPM4 is thought to play an etiopathogenetic role in certain tumor varieties such as prostate cancer and large B-cell lymphoma. In colon carcinoma, high TRPM4 protein expression was associated with unfavorable tumor characteristics (Kappel S et al. 2019).

TRPM4 expression might influence certain tumor cell behaviors, such as migration and invasion. However, the mechanisms remain unknown to date (Gao Y et al. 2019).

9-phenanthrol is a TRPM4 inhibitor. The effects of other selective small molecule inhibitors remain to be seen.

1. Farooqi A et al. (2011) TRPM channels: same ballpark, different players, and different rules in immunogenetics. Immunogenetics 63: 773-787
2. Gao Y et al (2019) TRPM4 channel and cancer. Cancer Lett 454:66-69.
3. Janin A et al. (2019) TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome. Europ J Med Genet 62: 10352
4. Kappel S et al (2019) TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells. Mol Oncol 13:2393-2405.
5. Kruse M et al (2009) Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest 119: 2737-2744.
6. Launay P et al (2002) TRPM4 is a Ca(2+)-activated nonselective cation channel mediating cell membrane depolarization. Cell 109: 397-407-2002.
7. Launay P et al. (2004) TRPM4 regulates calcium oscillations after T cell activation. Science 306: 1374-1377
8. Mathar I et al (2014) Handb Exp Pharmacol 222:461-487.
9. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
10. Stallmeyer B et al. (2012) Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances. Hum Mutat 33: 109-117
11. Vennekens R et al (2007) Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nature Immune 8: 312-320
12. Wang H et al (2019) Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratoderma. J Invest Derm 139: 1089-1097