TY - JOUR
T1 - ATP steal between cation pumps
T2 - A mechanism linking Na+ influx to the onset of necrotic Ca2+ overload
AU - Castro, J.
AU - Ruminot, I.
AU - Porras, O. H.
AU - Flores, C. M.
AU - Hermosilla, T.
AU - Verdugo, E.
AU - Venegas, F.
AU - Härtel, S.
AU - Michea, L.
AU - Barros, L. F.
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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.
AB - 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.
U2 - 10.1038/sj.cdd.4401852
DO - 10.1038/sj.cdd.4401852
M3 - Article
VL - 13
SP - 1675
EP - 1685
JO - CELL DEATH AND DIFFERENTIATION
JF - CELL DEATH AND DIFFERENTIATION
SN - 1350-9047
IS - 10
ER -