Glutamate-induced calcium loads: effects on energy metabolism and neuronal viability.

1. Glutamate-induced increases in intracellular free Ca2+ concentration ([Ca2+]i) were recorded from cultured rat hippocampal neurons with single cell microfluorometry. The [Ca2+]i increase did not correlate with glutamate-induced cell death, consistent with the idea that Ca2+ accumulates in an intracellular store, and that loading this store might be toxic. 2. Glutamate-induced Ca2+ loads were buffered by a low-affinity, high-capacity process that was inhibited by the mitochondrial uncoupling agent FCCP and modulated by intracellular Na+. 3. Glutamate-induced Ca2+ loads also produced an intracellular acidification. The acidification was prevented by the metabolic inhibitor 2-deoxyglucose, mimicked by Ba2+, and inhibited by microinjection of ruthenium red. 4. These data are consistent with the hypothesis that mitochondria sequester glutamate-induced Ca2+ loads producing a metabolic acidosis; metabolic stress may contribute to glutamate-induced neuronal death.