Overactivation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate andN-methyl-D-aspartate but not kainate receptors inhibits phosphatidylcholine synthesis before excitotoxic neuronal death

Glutamate receptor overactivation induces excitotoxic neuronal death, but t he contribution of glutamate receptor subtypes to this excitotoxicity is un clear. We have previously shown that excitotoxicity by NMDA receptor overac tivation is associated with choline release and inhibition of phosphatidylc holine synthesis. We have now investigated whether the ability of non-NMDA ionotropic glutamate receptor subtypes to induce excitotoxicity is related to the ability to inhibit phosphatidylcholine synthesis. alpha -Amino-3-hyd roxy-5-methytisoxazole-4-propionate (AMPA)-induced a concentration-dependen t increase in extracellular choline and inhibited phosphatidylcholine synth esis when receptor desensitization was prevented. Kainate released choline and inhibited phosphatidylcholine synthesis by an action at AMPA receptors, because these effects of kainate were blocked by the AMPA receptor antagon ist LY300164. Selective activation of kainate receptors failed to release c holine, even when kainate receptor desensitization was prevented. The inhib ition of phosphatidylcholine synthesis evoked by activation of nondesensiti zing AMPA receptors was followed by neuronal death. In contrast, specific k ainate receptor activation, which did not inhibit phosphatidylcholine synth esis, did not produce neuronal death. Choline release and inhibition of pho sphatidylcholine synthesis were induced by AMPA at non-desensitizing AMPA r eceptors well before excitotoxicity. Furthermore, choline release by AMPA r equired the entry of Ca2+ through the receptor channel. Our results show th at AMPA, but not kainate, receptor overactivation induces excitotoxic cell death, and that this effect is directly related to the ability to inhibit p hosphatidylcholine synthesis. Moreover, these results indicate that inhibit ion of phosphatidylcholine synthesis is an early event of the excitotoxic p rocess, downstream of glutamate receptor-mediated Ca2+ overload.