1.A.4.5.1
Mg²⁺-selective channel/kinase-1; Mg²⁺-ATP-regulated divalent cation channel, LTRPC7, TRPM7, or TRP-PLIK, of 1862 aas. Bradykinin regulates TRPM7 and its downstream target annexin-1 through a phospholipase C-dependent, protein kinase C-dependent and c-Src-dependent pathway that is cAMP-independent; effects are mediated through the bradykinin type 2 receptor (Callera et al. 2009).  TRPM7 is a Mg²⁺ sensor and transducer of signaling pathways during stressful environmental conditions. Its kinase can act on its own in chromatin remodeling processes, but TRPM6's kinase activity regulates intracellular trafficking of TRPM7 and TRPM7-dependent cell growth (Cabezas-Bratesco et al. 2015).  Syndecans (proteoglycans) regulate TRPC channels to control cytosolic calcium equilibria and consequent cell behavior. In fibroblasts, ligand interactions with heparan sulfate of syndecan-4 recruit cytoplasmic protein kinase C to target serine714 of TRPC7 with subsequent control of the cytoskeleton and the myofibroblast phenotype (Gopal et al. 2015).  May be associated with melanocytic tumors.  Phenanthrenes, naltriben derivatives, are stimulatory agonist of the TRPM7 channel (Liu et al. 2016). TRP7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells, and its activity is positively regulated by aldosterone and angiotensin II (He et al. 2005). TRPM7 plays an important role in cellular Ca²⁺, Zn²⁺ and Mg²⁺ homeostasis. The protein is  abundantly expressed in ameloblasts and, in the absence of TRPM7, dental enamel is hypomineralized. A role of TRPM7 channels in Ca²⁺ transport during amelogenesis is likely as it serves both as a modulator of Orai-dependent Ca²⁺ uptake and as an independent Ca²⁺ entry pathway, sensitive to pH (Kádár et al. 2021). Recurrent hemiplegic migraine attacks are accompanied by intractable hypomagnesemia due to a de novo TRPM7 gene variant (Lei et al. 2022). TrpM6 is palmitoylated on the C terminal side of its Trp domain, and palmitoylation controls ion channel activity of TrpM7; TrpM7 trafficking is also dependant on its palmitoylation (Gao et al. 2022). The TRPM7-A931T mutation, located in the S3 segment at the interface with the transmembrane region S4, generates an omega current that carries Na⁺ influx under physiological conditions. A931T produces hyperexcitability and a sustained Na⁺ influx in trigeminal ganglion neurons that may underlie pain in this kindred with trigeminal neuralgia (Gualdani et al. 2022). In addition to ion homeostasis, TrpM7 functions in hypomagnesemia, mitochondrial activities, and inflammation (Liu and Dudley 2023). TRPM7 regulates glioma cells' stemness through STAT3. Guo et al. 2023 showed that FOSL1 (271 aas) a cytoplasmic protein with Uniprot acc# P15407) is a response gene for TRPM7 and serves as an oncogene to promote glioma proliferation and invasion. They also showed that TRPM7 transactivates the FOSL1 gene through STAT3 and enhances glioma stemness (Guo et al. 2023). Expression profiling has identified TRPM7 and HER2 as potential targets for the combined treatment of cancer cells (Egawa et al. 2024).