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Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role of Ca2+ deficiency.

Authors
Yoon, WJ; Won, SJ; Ryu, BR; Gwag, BJ
Citation
Journal of neurochemistry, 85(2):525-533, 2003
Journal Title
Journal of neurochemistry
ISSN
0022-30421471-4159
Abstract
Blockade of ionotropic glutamate receptors induces neuronal cell apoptosis. We investigated if mitochondria-mediated death signals would contribute to neuronal apoptosis following administration of glutamate antagonists. The administration of MK-801 and CNQX (MK-801/CNQX), the selective antagonists of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors, produced widespread neuronal death in neonatal rat brain and cortical cell cultures. MK-801/CNQX-induced neuronal apoptosis was prevented by zVAD-fmk, a broad inhibitor of caspases, but insensitive to inhibitors of calpain or cathepsin D. Activation of caspase-3 was observed within 6-12 h and sustained over 36 h after exposure to MK-801/CNQX, which cleaved PHF-1 tau, the substrate for caspase-3. Activation of caspase-3 was blocked by high K+ and mimicked by BAPTA-AM, a selective Ca2+ chelator. Reducing extracellular Ca2+, but not Na+, activated caspase-3, suggesting an essential role of Ca2+ deficiency in MK-801/CNQX-induced activation of caspases. Cortical neurons treated with MK-801/CNQX triggered activation of caspase-9, release of cytochrome c from mitochondria, and translocation of Bax into mitochondria. The present study suggests that blockade of ionotropic glutamate receptors causes caspase-3-mediated neuronal apoptosis due to Ca2+ deficiency that is coupled to the sequential mitochondrial death pathway.
MeSH terms
6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacologyAnimalsApoptosis/drug effectsApoptosis/physiology*Calcium/deficiency*Calcium/metabolismCaspase 3Caspase 9Caspases/antagonists & inhibitorsCaspases/metabolismCells, CulturedCerebral Cortex/cytologyChelating Agents/pharmacologyCytochrome c Group/metabolismDizocilpine Maleate/pharmacologyEnzyme Inhibitors/pharmacologyExcitatory Amino Acid Antagonists/pharmacologyMiceNeurons/cytologyNeurons/drug effects*Neurons/metabolism*Potassium/pharmacologyProtein Transport/drug effectsProto-Oncogene Proteins/metabolismProto-Oncogene Proteins c-bcl-2*RatsRats, Sprague-DawleyReceptors, AMPA/antagonists & inhibitorsReceptors, AMPA/metabolismReceptors, Glutamate/drug effects*Receptors, Glutamate/metabolismReceptors, N-Methyl-D-Aspartate/antagonists & inhibitorsReceptors, N-Methyl-D-Aspartate/metabolismbcl-2-Associated X Protein
PMID
12675929
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > School of Medicine / Graduate School of Medicine > Medical Science
AJOU Authors
원, 석준곽, 병주
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