Zinc-induced Neurotoxicity Mediated by Transient Receptor Potential Melastatin 7 Channels

Abstract

Transient receptor potential melastatin 7 (TRPM7) channels are novel Ca 2؉ -permeable non-selective cation channels ubiquitously expressed. Activation of TRPM7 channels has been shown to be involved in cellular Mg 2؉ homeostasis, diseases caused by abnormal magnesium absorption, and in Ca 2؉ -mediated neuronal injury under ischemic conditions. Here we show strong evidence suggesting that TRPM7 channels also play an important role in cellular Zn 2؉ ] i measurement have been questionable. For example, previous studies reported that some indicators commonly used for calcium imaging, e.g. Calcium Green-1 and fura-2, are responsive to zinc with an extremely high affinity, and that specific zinc chelators reduced the intensity of calcium indicators (4 -7). These findings suggest that some of the biological effects previously assumed to be mediated by Ca 2ϩ may be mediated, at least partially, by zinc ions. Like calcium, recent studies have demonstrated that zinc ions play an important role in neuronal injuries associated with various neurological conditions (8, 9). The exact pathways mediating intracellular zinc accumulations and toxicity are, however, not clear.Zinc is one of the most crucial trace metals in cells. For example, zinc is required for the function of a broad range of enzymes involved in transcription, protein synthesis, and signal transductions (10). Although there are low levels of free zinc in cells, most zinc ions are bound to intracellular proteins (11). The mechanisms that affect the free zinc concentration are, therefore, pivotal for maintaining normal brain function. Although the extracellular fluid may contain up to several micromolar of zinc, intracellular zinc concentration ([Zn 2ϩ ] i ) is generally maintained at 10 Ϫ9 -10 Ϫ10 M (10, 12, 13). This steep gradient across the cell membrane is maintained primarily by zinc extrusion systems such as zinc transporters (ZnTs). At least 10 members of ZnTs, with different tissue distribution, have been identified in the ZnTs family. They promote the efflux of intracellular zinc into extracellular space or uptake of zinc into vesicles (14,15). In contrast to ZnTs, Zrt-and Irt-like proteins, or ZIPs, are known to transport zinc into the cells (14, 15). In addition, some calcium channels, e.g. voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate (NMDA) receptors, and amino-3-hydroxy-5-methyl-4-isoxazol propionate (AMPA)/kinate receptors have been reported to be zinc permeable (16,17). The activities of these channels thus affect intracellular zinc homeostasis and toxicity. Unfortunately, clinical trials using the antagonists of these channels failed to provide satisfactory neuroprotection (2, 3).Transient receptor potential melastatin 7 (TRPM7) is a member of the large TRP channel superfamily expressed in * This work was supported, in whole or in part, by National Institutes of Health Grants R01NS47506 and R01NS49470 and American Heart Association Grant 0840132N.

Taurine Inhibits K+-Cl− Cotransporter KCC2 to Regulate Embryonic Cl− Homeostasis via With-no-lysine (WNK) Protein Kinase Signaling Pathway

“…Plasmid Construction-pCAGGS-eGFP that carries enhanced GFP downstream of a CAG promoter (34,35) was kindly provided by Dr. J. Miyazaki (Okasa University, Osaka, Japan). For KCC2 expression, cDNA encoding FLAG-tagged KCC2 on pCMV-KCC2 (21, 36) was inserted into pCAGGS-eGFP.…”

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

“…The resulting increase in cytosolic Zn 2+ could result in toxic cytosolic concentrations (9). Conversely, reduction of TRPM7 expression protects animals from postischemia reperfusion (5), a condition typically accompanied by increased reactive oxygen species (ROS) and Zn…”

Transient receptor potential melastatin type 7 channels are involved in zinc-induced apoptosis in gastric cancer

“…The studies were performed using millimolar concentrations of zinc, which are several orders of magnitude higher than the physiological/pathophysiological concentrations of zinc (Monteilh-Zoller et al 2003;Frederickson et al 2005). Recently, Inoue et al (2010) pathologically relevant concentrations (Frederickson et al 2005), and, more importantly, in zinc-induced neuronal injury. They showed that in cultured mouse cortical neurons, TRPM7 was involved in Zn 2' -mediated neurotoxicity.…”

“…Notably, we demonstrated that human gastric adenocarcinoma cells express TRPM7 channels whose presence is essential for cell survival (Kim et al 2008). TRPM7 is, at present, the only known zinc-permeable channel among the TRP family of ion channels (Clapham 2003;Monteilh-Zoller et al 2003;Inoue et al 2010). It is reported that the zinc permeability for TRPM7 channels is 4-fold higher than for Ca 2' (Monteilh-Zoller et al 2003).…”