Group IIA secretory phospholipase A₂ (GIIA) mediates apoptotic death during NMDA receptor activation in rat primary cortical neurons

J. Neurochem. (2010) 112, 1574-1583. Phospholipases A₂ (PLA₂) 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 PLA₂ activity by flow cytometry, here we show that the group IIA secretory phospholipase A₂ isoform (GIIA) was specifically activated in cortical neurons following stimulation of N-methyl- d-aspartate glutamate receptor subtype (NMDAR). For activation, GIIA required Ca²⁺ 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.