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 2+ and divalent metal cations such as Ca 2+ , Zn 2+ , Cd 2+ , Mn 2+ , and Ni 2+ . TRPM7 channels are inhibited by cytosolic Mg 2+ , rendering them largely inactive in intact cells. The dependence of channel activity on extracellular Mg 2+ is less well studied. Here, we measured native TRPM7 channel activity in Jurkat T cells maintained in external Mg 2+ concentrations varying between 400 nM and 1.4 mM for 1-3 days, obtaining an IC 50 value of 54 μM. Maintaining the cells in 400 nM or 8 μM [Mg 2+ ] o resulted in almost complete activation of TRPM7 in intact cells, due to cytosolic Mg 2+ depletion. A total of 1.4 mM [Mg 2+ ] o was sufficient to fully eliminate the basal current. Submillimolar concentrations of amiloride prevented cellular Mg 2+ depletion but not loading. We investigated whether the cytotoxicity of TRPM7 permeant metal ions Ni 2+ , Zn 2+ , Cd 2+ , Co 2+ , Mn 2+ , Sr 2+ , and Ba 2+ requires TRPM7 channel activity. Mg 2+ loading modestly reduced cytotoxicity of Zn 2+ , Co 2+ , Ni 2+ , and Mn 2+ but not of Cd 2+ . Channel blocker NS8593 reduced Co 2+ and Mn 2+ but not Cd 2+ or Zn 2+ cytotoxicity and interfered with Mg 2+ loading as evaluated by TRPM7 channel basal activity. Ba 2+ and Sr 2+ 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 2+ entry requires TRPM7 channels.
Luu, C. T.,
& Kozak, J. A.
(2020). TRPM7 Channel Activity in Jurkat T Lymphocytes During Magnesium Depletion and Loading: Implications for Divalent Metal Entry and Cytotoxicity. Pflugers Archiv : European journal of physiology, 472 (11), 1589-1606.