ATP steal between cation pumps: a mechanism linking Na+ influx to the onset of necrotic Ca2+ overload

• Published in: Cell death and differentiation Vol. 13; no. 10; pp. 1675 - 1685
• Main Authors: Castro, J, Ruminot, I, Porras, O H, Flores, C M, Hermosilla, T, Verdugo, E, Venegas, F, Härtel, S, Michea, L, Barros, L F
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-10-2006
• Subjects: Adenosine Triphosphate - metabolism; Animals; Calcium - metabolism; Calcium-Transporting ATPases - metabolism; Cation Transport Proteins - metabolism; Cell death; Cell Line; Cell Membrane - metabolism; Dogs; Enzymes; HeLa Cells; Humans; Hydrogen peroxide; Metabolism; Models, Biological; Necrosis; Oxidative Stress; Permeability; Physiology; Sodium - metabolism; Sodium-Potassium-Exchanging ATPase - metabolism; Chile
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4401852

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.