TRPM7

TRPM7 is the acronym for "Transient receptor potential cation channel, subfamily M, member 7". TRPM7 has been found in every mammalian tissue studied to date (Fleig A et al. 2014) and is thus ubiquitously expressed. Like most TRPMs, the cation channel is permeable to calcium and magnesium. TRPM7 and TRPM6 are critically involved in maintaining whole-body and cellular Mg2+ homeostasis and ensuring normal function of organs such as the heart and kidney (Cuffe JS et al 2015). The gene of the same name is located on chromosome 15q21.2. TRPM7 is a fusion protein with an ion transport domain and an enzymatically active kinase domain(Chanzyme = channel + kinase). The kinase activity is essential for channel function.

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 of a cell. 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.

Ion transport: The particular biophysical properties of the protein, enable bivalent ion transport. TRPM7 is involved in a variety of (patho-)physiological processes. With its prominent role in cellular and systemic magnesium absorption and homeostasis, TRPM7 emerges as a key player in embryonic development, ischemic processes, cardiovascular diseases and tumor diseases. TRPM7 is permeable to a number of trace metals such as Zn2+, Ni2+, Ba2+, Co2+, Mn2+, Sr2+ and Cd2+ in addition to Ca2+ and Mg2+. A distinctive feature of the channel is that it is inhibited by even low millimolar concentrations of intracellular Mg2+. However, how intracellular Mg2+ counteracts Mg2+ influx is currently unclear.

TRPM7 and melanocytes /melanoma cells: TRPM7, like TRPM1, TRPM2, and TRPM8, is expressed by melanocytes and by melanoma cells. Therefore, these TRP- channels (TRPM1 is considered the most important TRP channel) are thought to play an important role in melanocyte function and in the pathophysiology of malignant melanoma. First, highly metastatic, undifferentiated melanomas were found to have decreased expression of TRPM1 compared to benign, highly differentiated melanocytic nevi. Also, TRPM1 expression correlates positively with melanocyte differentiation status and inversely with malignant melanoma aggressiveness and tumor thickness. In contrast to TRPM1, increased expression levels of TRMP7 were found in metastatic melanoma cells.

Macrophage activity: Cytosolic Ca2+ increases mediated by TRPM7 are essential for lipopolysaccharide (LPS)-induced macrophage activation and activity. LPS triggers TRPM7-dependent Ca2+ increases that are essential for TLR4 endocytosis and subsequent activation of the transcription factor IRF3. TRPM7-deficient macrophages exhibit major deficiencies in LPS-induced transcriptional programs due to their inability to produce IL-1β and other key pro-inflammatory cytokines (Schappe MS et al. 2018).

Inhibition of channel function: In addition to Mg2+, TRPM7 can be inhibited by other divalent cations, polyamines and protons, as well as purine and pyrimidine nucleotide triphosphates.

Mutation of an identified autophosphorylation site in TRPM7 is associated with certain types of neurodegenerative diseases in patients from the Western Pacific Islands .

In zebrafish, loss of function of TRPM7 (drTRPM7) manifests in a range of nonlethal physiological dysfunctions (Jansen C et al. 2016).

1. Chubanov V et al (2004) Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Nat Acad Sci 101: 2894-2899
2. Cuffe JS et al (2015) Differential mRNA expression and glucocorticoid-mediated regulation of TRPM6 and TRPM7 in the heart and kidney throughout murine pregnancy and development. PLoS One:e0117978.
3. Farooqi A et al. (2011) TRPM channels: same ballpark, different players, and different rules in immunogenetics. Immunogenetics 63: 773-787
4. Fleig a et al. (2014) TRPM7. Handb Exp Pharmacol 222:521-546.
5. Hantute-Ghesquier A et al (2018) TRPM Family Channels in Cancer. Pharmaceuticals (Basel) 11:58.
6. Jansen C et al (2016) The coiled-coil domain of zebrafish TRPM7 regulates Mg-nucleotide sensitivity. Sci Rep 6:33459.
7. Luongo F et al. (2018) TRPM6 is essential for Magnesium Uptake and Epithelial Cell Function in the Colon. Nutrients 18:784.
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. Schappe MS et al. (2018) Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation. Immunity 48:59-74.
11. Shari L et al (2010) Nairn, in Handbook of Cell Signaling (Second Edition), 2010.
12. van der Wijst J et al (2014) Mg2+ homeostasis: the balancing act of TRPM6. Curr Opin Nephrol Hypertens 23:361-369.