Group IIA secretory phospholipase A2 (GIIA) mediates apoptotic death during NMDA receptor activation in rat primary cortical neurons.
Phospholipases A(2) (PLA(2)) participate in neuronal death signalling pathways because of their ability to release lipid mediators, although the contribution of each isoform and mechanism of neurotoxicity are still elusive. Using a novel fluorogenic method to assess changes in a PLA(2) activity by flow cytometry, here we show that the group IIA secretory phospholipase A(2) isoform (GIIA) was specifically activated in cortical neurons following stimulation of N-methyl-d-aspartate glutamate receptor subtype (NMDAR). For activation, GIIA required Ca(2+) and reactive oxygen/nitrogen species, and inhibition of its activity fully prevented NMDAR-mediated neuronal apoptotic death. Superoxide, nitric oxide or peroxynitrite donors stimulated GIIA activity, which mediated neuronal death. Intriguingly, we also found that GIIA activity induced mitochondrial superoxide production after NMDAR stimulation. These results reveal a novel role for GIIA in excitotoxicity both as target and producer of superoxide in a positive-loop of activation that may contribute to the propagation of neurodegeneration.
Chiricozzi
Elena
E
Department of Internal Medicine, Biochemistry Section, University of Perugia, Perugia, Italy.
Fernandez-Fernandez
Seila
S
Nardicchi
Vincenza
V
Almeida
Angeles
A
Bolaños
Juan Pedro
JP
Goracci
Gianfrancesco
G
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D018698:Glutamic Acid / Q000494:pharmacology; D054501:Group II Phospholipases A2 / Q000378:metabolism* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology
D017304:Annexin A5; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D019820:Xanthine; D018698:Glutamic Acid; C002385:linsidomine; D008981:Molsidomine; D014969:Xanthine Oxidase; D054501:Group II Phospholipases A2; D002118:Calcium