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Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax‐cytochrome C‐caspase pathway: the causative role of Ca 2+ deficiency
Author(s) -
Yoon W. J.,
Won S. J.,
Ryu B. R.,
Gwag B. J.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01724.x
Subject(s) - cnqx , ionotropic effect , kainate receptor , ampa receptor , microbiology and biotechnology , cytochrome c , glutamate receptor , chemistry , excitotoxicity , biology , mitochondrion , receptor , biochemistry
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 α‐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 Ca 2+ chelator. Reducing extracellular Ca 2+ , but not Na + , activated caspase‐3, suggesting an essential role of Ca 2+ 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 Ca 2+ deficiency that is coupled to the sequential mitochondrial death pathway.