PHOSPHATIDYLCHOLINE-SPECIFIC PHOSPHOLIPASE-C REGULATES GLUTAMATE-INDUCED NERVE-CELL DEATH

Phosphatidylcholine-specific phospholipase C (PC-PLC) is a necessary i ntermediate in transducing apoptotic signals for tumor necrosis factor and Fas/Apo-1 ligands in nonneuronal cells. The data presented here s how that PC-PLC also is required in oxidative glutamate-induced progra mmed cell death of both immature cortical neurons and a hippocampal ne rve cell line, HT22. In oxidative glutamate toxicity, which is distinc t from excitotoxicity, glutamate interferes with cystine uptake by blo cking the cystine/glutamate antiporter, indirectly causing a depletion of intracellular glutathione, A PC-PLC inhibitor blocks oxidative glu tamate toxicity, and exogenous PC-PLC potentiates glutamate toxicity, The inhibition of PC-PLC uncouples the cystine uptake from glutamate i nhibition, allowing the maintenance of glutathione synthesis and cell viability. These data suggest that PC-PLC modulates neuronal cell deat h through a mechanism that is distinct from that involved in nonneuron al apoptosis.