Phosphatidylcholine-specific phospholipase C regulates glutamate-induced nerve cell death.
Phosphatidylcholine-specific phospholipase C (PC-PLC) is a necessary intermediate in transducing apoptotic signals for tumor necrosis factor and Fas/Apo-1 ligands in nonneuronal cells. The data presented here show that PC-PLC also is required in oxidative glutamate-induced programmed cell death of both immature cortical neurons and a hippocampal nerve cell line, HT22. In oxidative glutamate toxicity, which is distinct from excitotoxicity, glutamate interferes with cystine uptake by blocking the cystine/glutamate antiporter, indirectly causing a depletion of intracellular glutathione. A PC-PLC inhibitor blocks oxidative glutamate toxicity, and exogenous PC-PLC potentiates glutamate toxicity. The inhibition of PC-PLC uncouples the cystine uptake from glutamate inhibition, allowing the maintenance of glutathione synthesis and cell viability. These data suggest that PC-PLC modulates neuronal cell death through a mechanism that is distinct from that involved in nonneuronal apoptosis.
Li
Y
Y
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Maher
P
P
Schubert
D
D
D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D017209:Apoptosis; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000633:toxicity; D002460:Cell Line; D003553:Cystine / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000963:Antimetabolites; D001952:Bridged-Ring Compounds; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors; D013859:Thiocarbamates; D013871:Thiones; D018698:Glutamic Acid; D003553:Cystine; D019328:Buthionine Sulfoximine; C046498:tricyclodecane-9-yl-xanthogenate; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C