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.
Thayer
S A
SA
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.
Wang
G J
GJ
D000818:Animals; D001464:Barium / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003592:Cytophotometry; D003847:Deoxyglucose / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; D001464:Barium; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D018698:Glutamic Acid; C053672:selfotel; D003847:Deoxyglucose; D012964:Sodium; D002118:Calcium