Abstract

We set out to identify molecular mechanisms underlying the onset of necrotic Ca 2+ overload, triggered in two epithelial cell lines by oxidative stress or metabolic depletion. As reported earlier, the overload was inhibited by extracellular Ca 2+ chelation and the cation channel blocker gadolinium. However, the surface permeability to Ca 2+ was reduced by 60%, thus discarding a role for Ca 2+ channel/carrier activation. Instead, we registered a collapse of the plasma membrane Ca 2+ ATPase (PMCA). Remarkably, inhibition of the Na +/K + ATPase rescued the PMCA and reverted the Ca 2+ rise. Thermodynamic considerations suggest that the Ca 2+ overload develops when the Na +/K + ATPase, by virtue of the Na + overload, clamps the ATP phosphorylation potential below the minimum required by the PMCA. In addition to providing the mechanism for the onset of Ca 2+ overload, the crosstalk between cation pumps offers a novel explanation for the role of Na + in cell death. © 2006 Nature Publishing Group. All rights reserved.