Disease relevance of TRPM7

• Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia [1].
• A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders [2].
• TRPM7 currents are also inhibited by stimulating endogenous muscarinic receptors, which is mediated by G(i) because the inhibitory effect is blunted by pertussis toxin [3].
• TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia [4].
• Thus, future treatment of ischemic brain injury may need to include strategies that inhibit or modulate TRPM7 activity [5].

Psychiatry related information on TRPM7

• Our data suggest that PIP(2) imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic Abeta42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions [6].

High impact information on TRPM7

• Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7 [7].
• In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death [4].
• Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role [4].
• Targeted deletion of LTRPC7 in DT-40 B cells was lethal, indicating that LTRPC7 has a fundamental and nonredundant role in cellular physiology [8].
• Our data indicate that LTRPC7, by virtue of its sensitivity to physiological Mg.ATP levels, may be involved in a fundamental process that adjusts plasma membrane divalent cation fluxes according to the metabolic state of the cell [8].

Chemical compound and disease context of TRPM7

• Identification of the gene defect in hypomagnesemia with secondary hypocalcemia recently elucidated transient receptor potential melastatin 6 (TRPM6) as the gatekeeper in transepithelial Mg(2+) transport, whereas its homolog, TRPM7, is implicated in cellular Mg(2+) homeostasis [9].

Biological context of TRPM7

• Deletion of TRPM7 in DT40 B-lymphocytes causes growth arrest, Mg(2+) deficiency, and cell death within 24-48 h [10].
• Amazingly, in analogy to TRPM6-deficient patients who can live a normal life if provided with a Mg(2+)-rich diet, TRPM7-deficient DT40 B-lymphocytes show wild type cell growth if supplied with 5-10 mm Mg(2+) concentrations in their extracellular medium [10].
• The TRPM7 channel is inactivated by PIP(2) hydrolysis [11].
• Reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry all showed abundant and localized expression of TRPM7 messenger RNA and protein in mouse small intestine [12].
• We found a TRPM7 variant in a subset of ALS-G and PD-G patients that produces a protein with a missense mutation, T1482I [2].

Anatomical context of TRPM7

• The aim here was to show that the nonselective cation channel in interstitial cells of Cajal in mouse small intestine has properties essentially identical to those of murine TRPM7, heterologously expressed in human embryonic kidney cells [12].
• The N-terminal region plays a crucial role in interaction of annexin 1 with other proteins and membranes, and therefore, phosphorylation of annexin 1 at Ser5 by TRPM7 kinase may modulate function of annexin 1 [13].
• LPC may induce Ca2+ influx via L-type Ca2+ channels and DMPH seems to induce Ca2+ influx through TRPM7 in U937 human monocytes [14].
• We also confirmed the presence of TRPM7 and absence of TRPM3 in U937 cells [14].
• TRPM7 is required for cell viability and has been proposed recently to mediate stress-induced cell death in the central nervous system [15].

Associations of TRPM7 with chemical compounds

• Our data demonstrate that TRPM6 requires TRPM7 for surface expression in HEK-293 cells and also that TRPM6 is capable of cross-phosphorylating TRPM7 as assessed using a phosphothreonine-specific antibody but not vice versa [10].
• Numerous experimental approaches demonstrated that phosphatidylinositol 4,5-bisphosphate (PIP(2)), the substrate of PLC, is a key regulator of TRPM7 [11].
• The kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC) [11].
• Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein containing both channel and kinase domains that has been proposed to be involved in the homeostatic regulation of intracellular Ca2+, Mg2+, and trace metal ion concentration [2].
• Phosphorylation of annexin 1 by TRPM7 kinase occurs at a conserved serine residue (Ser5) located within the N-terminal amphipathic alpha-helix of annexin 1 [13].

Regulatory relationships of TRPM7

• We show that TRPM7 deficiency in DT40 cells cannot be complemented by heterologously expressed TRPM6 [10].
• TRPM7 Regulates Cell Adhesion by Controlling the Calcium-dependent Protease Calpain [16].

Other interactions of TRPM7

• Together, our data suggest an important contribution of TRPM6/TRPM7 heterooligomerization for the biological role of TRPM6 in epithelial magnesium absorption [1].
• TRPM6 and TRPM7 belong to the melastatin-related TRPM subfamily of TRP channels whose eight members exhibit a significant diversity in domain structure as well as cation selectivity and activation mechanisms [17].
• Electrophysiological recordings demonstrated the presence of functional TRPM7, a constitutively active cation channel sensitive to intracellular Mg(2+), and TRPM2, an ADP-ribose-dependent cation channel activated by oxidative stress [18].
• Here we demonstrate that TRPM7, a member of the transient receptor potential (TRP) ion channel family, resides in the membrane of synaptic vesicles of sympathetic neurons, forms molecular complexes with the synaptic vesicle proteins synapsin I and synaptotagmin I, and directly interacts with synaptic vesicular snapin [19].
• Evaluation of the expression of several members of the SLC41 (solute carrier family 41) family, which exhibit homology with the MgtE class of prokaryotic putative bivalent-cation transporters, demonstrated that one, SLC41A2 (solute carrier family 41 member 2), is expressed in both wild-type and TRPM7-deficient DT40 cells [20].

Analytical, diagnostic and therapeutic context of TRPM7

• METHODS: The patch-clamp technique for whole-cell recording was used in cultured or single interstitial cells of Cajal. TRPM7-specific small interfering RNAs were used for specific inhibition of TRPM7 [12].
• Reverse transcriptase polymerase chain reaction and immunoblotting demonstrated TRPM7 presence in VSMCs (membrane and cytosol) [21].
• The TRPM7 mRNA was detected by RT-PCR method [22].
• EA could reverse the overexpression of TRPM7 in cerebral ischemia/reperfusion rats [22].
• The effect of electroacupuncture (EA) on TRPM7 mRNA expression of focal cerebral ischemia in rats and further the role of EA in the relationship between TRPM7 and trkA pathway was investigated [22].

References