Down-regulation of GluR2 is associated with Ca2+-dependent protease activities in kainate-induced apoptotic cell death in cultured [correction of culturd] rat hippocampal neurons.
In the present study, the molecular mechanisms underlying kainate-induced neurotoxicity were characterized in cultured rat hippocampal neurons. Long-term exposure to kainate caused typically apoptotic cell death, which was accompanied by the accumulation of calcium, marked down-regulation of GluR2 subunit, and the activation of calpain and caspase-3. All these alterations were prevented by alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist CNQX, but not by NMDA receptor antagonist MK801 and membrane L-type calcium channel antagonist nifedipine. In the presence of cyclothiazide, kainate-induced neurotoxicity was significantly enhanced. Inhibition of either caspases by zVAD-fmk or calpains by calpeptin protected neurons from neurotoxicity. These results suggest that long-term exposure of hippocampal neurons to kainate causes apoptosis, whose mechanisms involve multiple Ca(2+)-dependent cascades, in which AMPA receptor subunits may be targets for Ca(2+)-activated protease-mediated degradation during kainate-induced neuron apoptosis.
Li
Shu-Yan
SY
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Xue Yuan Road 38, Beijing 100083, PR China.
Ni
Ju-Hua
JH
Xu
De-Sheng
DS
Jia
Hong-Ti
HT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid