The Mg2+ transporter MagT1 partially rescues cell growth and Mg2+ uptake in cells lacking the channel-kinase TRPM7

University of Colorado, Denver, Colorado, United States
FEBS letters (Impact Factor: 3.17). 05/2011; 585(14):2275-8. DOI: 10.1016/j.febslet.2011.05.052
Source: PubMed


Magnesium (Mg(2+)) transport across membranes plays an essential role in cellular growth and survival. TRPM7 is the unique fusion of a Mg(2+) permeable pore with an active cytosolic kinase domain, and is considered a master regulator of cellular Mg(2+) homeostasis. We previously found that the genetic deletion of TRPM7 in DT40 B cells results in Mg(2+) deficiency and severe growth impairment, which can be rescued by supplementation with excess extracellular Mg(2+). Here, we show that gene expression of the Mg(2+) selective transporter MagT1 is upregulated in TRPM7(-/-) cells. Furthermore, overexpression of MagT1 in TRPM7(-/-) cells augments their capacity to uptake Mg(2+), and improves their growth behavior in the absence of excess Mg(2+).

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Available from: Anne-Laure Perraud
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    • "The view that TRPM7 plays a role in maintaining cellular Mg 2+ homeostasis mainly centers on the observation that TRPM7- deficiency leads to reduced [Mg 2+ ] i in a number of cell types (Abed and Moreau, 2009; Chen et al., 2012; He et al., 2005; Rybarczyk et al., 2012; Zhang et al., 2011). In addition, defects in cell growth, cytoskeletal organization or migration due to TRPM7-deficiency in cultured cells, embryonic stem cells and Xenopus embryos, were largely rescued by either Mg 2+ supplementation (to supraphysiological levels) or by expression of the Mg 2+ -transporters SLC41A2 or MagT1 (Abed and Moreau, 2009; Callera et al., 2009; Deason-Towne et al., 2011; Liu et al., 2011; Ryazanova et al., 2010; Rybarczyk et al., 2012; Schmitz et al., 2003; Su et al., 2011). In contrast, studies by the Clapham lab indicate that TRPM7 is not critically required for cellular Mg 2+ homeostasis. "
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    ABSTRACT: Transient Receptor Potential (TRP) cation channels represent a large and diverse family of ion channels that act as important transducers of sensory information. The Melastatin subfamily member TRPM7 has garnered much interest due to its functional kinase domain; a unique feature among ion channels. TRPM7 primarily conducts Ca2+ and Mg2+ and its activity is regulated by intracellular Mg2+, phospholipase C-mediated signaling and mechanical cues. A growing number of studies emphasize a regulatory role for TRPM7 in proliferation and cell survival as well as cytoskeletal reorganization during adhesion and migration. Knockout approaches in animal models have revealed that TRPM7 significantly contributes to embryonic development and organogenesis. In addition, a role for TRPM7 to the pathophysiology of several diseases has become evident in recent years. Here, we discuss how recent insights have contributed to our understanding of TRPM7 function and regulation in health and disease.
    Full-text · Article · Jul 2014 · European Journal of Cell Biology
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    • "Transient receptor potential melastatin 7 channels are non-selective cation channels with predominant permeability for Ca2+ and Mg2+. Activation of TRPM7 is implicated in diverse physiological and pathological processes, such as Mg2+ homeostasis [3–6], cell viability, growth and proliferation [7–9], anoxic neuronal cell death [10], synaptic transmission, and cell adhesion [11, 12]. It has been reported that TRPM7 is abundantly expressed in a variety of human carcinoma cells, including gastric adenocarcinoma cells [13], lung cancer cells [14], and breast cancer cells [15]. "
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    ABSTRACT: Breast cancer is one of the most common cancer and remains the leading cause of cancer-related deaths in women. There is increasing evidence suggesting that TRPM7 plays a pivotal role in breast cancer progression and metastasis. In this study, a case–control study was carried out to investigate the effects of SNPs in TRPM7 genes in the development of breast cancer in Han Population of Northeast China. A total of six SNPs (rs8042919, rs4775899, rs11635825, rs7173321, rs616256, and rs11070795) were chosen and genotyped. Genotypes were analyzed using a single-base primer extension assay. Chi-square (χ 2) test was used to analyze statistical difference between control and patient groups in genotype and allele frequencies. The genotype-specific risks and allele frequencies of haplotypes in breast cancer patients and controls were estimated by OR and 95 % confidence intervals. The G allele of rs8042919 was associated with a reduced disease risk. The G allele of rs7173321 and particularly its homozygous GG genotype are associated with an increased breast cancer risk. Two of the TRPM7 SNPs (rs8042919 and rs7173321) are associated with breast cancer patients in Han Population of Northeast China.
    Preview · Article · Jul 2014 · Medical Oncology
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    • "Given the recent emergence of data with other vertebrate magnesium transporters [5], [6], [7], [10], we speculated that an orthologous Mg2+ transporter, MgtE, could functionally compensate for the absence of TRPM7. We chose to evaluate B. subtilis MgtE specifically based on its homology with the SLC41 family of vertebrate transporters, of which two members have been characterized in-depth [5], [6], [14], [18]. "
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    ABSTRACT: Recent studies have shown that the vertebrate magnesium transporters Solute carrier family 41, members 1 and 2 (SLC41A1, SLC41A2) and Magnesium transporter subtype 1 (MagT1) can endow vertebrate B-cells lacking the ion-channel kinase Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) with a capacity to grow and proliferate. SLC41A1 and SLC41A2 display distant homology to the prokaryotic family of Mg(2+) transporters, MgtE, first characterized in Bacillus subtilis. These sequence similarities prompted us to investigate whether MgtE could potentially compensate for the lack of TRPM7 in the vertebrate TRPM7-deficient DT40 B-cell model system. Here, we report that overexpression of MgtE is able to rescue the growth of TRPM7-KO DT40 B-cells. However, contrary to a previous report that describes regulation of MgtE channel gating by Mg(2+) in a bacterial spheroplast model system, whole cell patch clamp analysis revealed no detectable current development in TRPM7-deficient cells expressing MgtE. In addition, we observed that MgtE expression is strongly downregulated at high magnesium concentrations, similar to what has been described for its vertebrate homolog, SLC41A1. We also show that the N-terminal cytoplasmic domain of MgtE is required for normal MgtE channel function, functionally confirming the predicted importance of this domain in regulation of MgtE-mediated Mg(2+) entry. Overall, our findings show that consistent with its proposed function, Mg(2+) uptake mediated by MgtE is able to restore cell growth and proliferation of TRPM7-deficient cells and supports the concept of functional homology between MgtE and its vertebrate homologs.
    Full-text · Article · Sep 2012 · PLoS ONE
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