TRPM7 channel activity in Jurkat T lymphocytes during magnesium depletion and loading: implications for divalent...

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 Mg²⁺ and divalent metal cations such as Ca²⁺, Zn²⁺, Cd²⁺, Mn²⁺, and Ni²⁺. TRPM7 channels are inhibited by cytosolic Mg²⁺, rendering them largely inactive in intact cells. The dependence of channel activity on extracellular Mg²⁺ is less well studied. Here, we measured native TRPM7 channel activity in Jurkat T cells maintained in external Mg²⁺ concentrations varying between 400 nM and 1.4 mM for 1-3 days, obtaining an IC₅₀ value of 54 μM. Maintaining the cells in 400 nM or 8 μM [Mg²⁺]_o resulted in almost complete activation of TRPM7 in intact cells, due to cytosolic Mg²⁺ depletion. A total of 1.4 mM [Mg²⁺]_o was sufficient to fully eliminate the basal current. Submillimolar concentrations of amiloride prevented cellular Mg²⁺ depletion but not loading. We investigated whether the cytotoxicity of TRPM7 permeant metal ions Ni²⁺, Zn²⁺, Cd²⁺, Co²⁺, Mn²⁺, Sr²⁺, and Ba²⁺ requires TRPM7 channel activity. Mg²⁺ loading modestly reduced cytotoxicity of Zn²⁺, Co²⁺, Ni²⁺, and Mn²⁺ but not of Cd²⁺. Channel blocker NS8593 reduced Co²⁺ and Mn²⁺ but not Cd²⁺ or Zn²⁺ cytotoxicity and interfered with Mg²⁺ loading as evaluated by TRPM7 channel basal activity. Ba²⁺ and Sr²⁺ 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 Mg²⁺ entry requires TRPM7 channels.