ATP steal between cation pumps: a mechanism linking Na+ influx to the onset of necrotic Ca2+ overload.
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.
Castro
J
J
Centro de Estudios Científicos CECS, Casilla 1469, Valdivia, Chile.
Ruminot
I
I
Porras
O H
OH
Flores
C M
CM
Hermosilla
T
T
Verdugo
E
E
Venegas
F
F
Härtel
S
S
Michea
L
L
Barros
L F
LF
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009336:Necrosis; D018384:Oxidative Stress; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D027682:Cation Transport Proteins; D000255:Adenosine Triphosphate; D012964:Sodium; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium