Abstract
We set out to identify molecular mechanisms underlying the onset of necrotic Ca2+ overload, triggered in two epithelial cell lines by oxidative stress or metabolic depletion. As reported earlier, the overload was inhibited by extracellular Ca2+ chelation and the cation channel blocker gadolinium. However, the surface permeability to Ca2+ was reduced by 60%, thus discarding a role for Ca2+ channel/carrier activation. Instead, we registered a collapse of the plasma membrane Ca2+ ATPase (PMCA). Remarkably, inhibition of the Na+/K+ ATPase rescued the PMCA and reverted the Ca2+ rise. Thermodynamic considerations suggest that the Ca2+ 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 Ca2+ overload, the crosstalk between cation pumps offers a novel explanation for the role of Na+ in cell death.
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Abbreviations
- KRH:
-
Krebs–Ringer–Hepes buffer
- NCX:
-
Na+/Ca2+ exchanger
- PMCA:
-
plasma membrane Ca2+ ATPase
- VOCC:
-
voltage-operated Ca2+ channel
- NVI:
-
necrotic volume increase
- LDH:
-
lactate dehydrogenase
- PI:
-
propidium iodide
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Acknowledgements
IR, CF and EV are students at the Universidad Austral de Chile. We thank Karen Everett for critical reading of the manuscript. This work was funded by Fondecyt Grants 1020648 and 1051082 (to LFB), 1050690 (to LM) and 3030065 (to SH). The Centro de Estudios Científicos (CECS) receives institutional support from Empresas CMPC, the Millenium Science Initiative, Fundación Andes and the Tinker Foundation.
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Castro, J., Ruminot, I., Porras, O. et al. ATP steal between cation pumps: a mechanism linking Na+ influx to the onset of necrotic Ca2+ overload. Cell Death Differ 13, 1675–1685 (2006). https://doi.org/10.1038/sj.cdd.4401852
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DOI: https://doi.org/10.1038/sj.cdd.4401852
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