TRPM7 Channel Activity in Jurkat T Lymphocytes During Magnesium Depletion and Loading: Implications for Divalent Metal Entry and Cytotoxicity

TRPM7 is a cation channel-protein kinase highly expressed in T lymphocytes and other immune cells. It has been proposed to constitute a cellular entry pathway for Mg and divalent metal cations such as Ca, Zn, Cd, Mn, and Ni. TRPM7 channels are inhibited by cytosolic Mg, rendering them largely inactive in intact cells. The dependence of channel activity on extracellular Mg is less well studied. Here, we measured native TRPM7 channel activity in Jurkat T cells maintained in external Mg concentrations varying between 400 nM and 1.4 mM for 1-3 days, obtaining an IC value of 54 μM. Maintaining the cells in 400 nM or 8 μM [Mg] resulted in almost complete activation of TRPM7 in intact cells, due to cytosolic Mg depletion. A total of 1.4 mM [Mg] was sufficient to fully eliminate the basal current. Submillimolar concentrations of amiloride prevented cellular Mg depletion but not loading. We investigated whether the cytotoxicity of TRPM7 permeant metal ions Ni, Zn, Cd, Co, Mn, Sr, and Ba requires TRPM7 channel activity. Mg loading modestly reduced cytotoxicity of Zn, Co, Ni, and Mn but not of Cd. Channel blocker NS8593 reduced Co and Mn but not Cd or Zn cytotoxicity and interfered with Mg loading as evaluated by TRPM7 channel basal activity. Ba and Sr were neither detectably toxic nor permeant through the plasma membrane. These results indicate that in Jurkat T cells, entry of toxic divalent metal cations primarily occurs through pathways distinct from TRPM7. By contrast, we found evidence that Mg entry requires TRPM7 channels.