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. 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 1-2 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. 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.
performed extensive molecular dynamics simulations and obtained the atomistic and dynamic details of this unique tethered mechanosensitive channel opening in response to the compression of the intracellular domain while remaining closed under an intracellular stretch. Under intracellular compression, the ankyrin repeat region undergoes a significant conformational change and passes the mechanical force to the linker helices like a spring with a force constant of 3.3 pN/nm. The linker helix region acts as a bridge between the ankyrin repeats and TRP domain and passes the force onto the TRP domain, which then undergoes a clockwise rotation and slight tilt that leads to the opening of the channel. We provide a clear picture of how a pushing force opens the mechanosensitive ion channel NompC, supported by electrophysiology experiment. We think this might be a universal gating mechanism of similar tethered mechanosensitive ion channels, enabling cells to feel and respond to compression or shrinking.
The original article was published with an error. In Figure 9b there are 3 typographical errors: instead of the Greek mu letter it shows the unconverted data. Should be 8 uM, 20 uM and 400 uM. The correct Figure 9 is presented here. The Original article has been corrected.
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