TY - JOUR
T1 - Nuclear translocation of nuclear transcription factor-κB by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons
AU - De Erausquin, Gabriel A.
AU - Hyrc, Krzyztof
AU - Dorsey, David A.
AU - Mamah, Daniel
AU - Dokucu, Mehmet
AU - Mascó, Daniel H.
AU - Walton, Timothy
AU - Dikranian, Krikor
AU - Soriano, Mario
AU - García Verdugo, José Manuel
AU - Goldberg, Mark P.
AU - Dugan, Laura L.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor κB (NFκB) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) resulted in a number of changes that occurred selectively in dopaminergic neurons, including persistent elevation in intracellular Ca2+ monitored with Fura-2, and a significant increase in intramitochondrial oxidation of dihydrorhodamine 123, probably associated with transient increase of mitochondrial permeability, cytochrome c release, nuclear translocation of NFκB, and transcriptional activation of the oncogene p53. Interruption of any of these steps by specific antagonists prevented neurite pruning and programmed cell death. In contrast, cell death was not prevented by caspase antagonists and only partly prevented by nitric-oxide synthase inhibitors. This signal transduction pathway might be a contributing mechanism in ongoing neuronal death in Parkinson disease.
AB - We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor κB (NFκB) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) resulted in a number of changes that occurred selectively in dopaminergic neurons, including persistent elevation in intracellular Ca2+ monitored with Fura-2, and a significant increase in intramitochondrial oxidation of dihydrorhodamine 123, probably associated with transient increase of mitochondrial permeability, cytochrome c release, nuclear translocation of NFκB, and transcriptional activation of the oncogene p53. Interruption of any of these steps by specific antagonists prevented neurite pruning and programmed cell death. In contrast, cell death was not prevented by caspase antagonists and only partly prevented by nitric-oxide synthase inhibitors. This signal transduction pathway might be a contributing mechanism in ongoing neuronal death in Parkinson disease.
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U2 - 10.1124/mol.63.4.784
DO - 10.1124/mol.63.4.784
M3 - Article
C2 - 12644578
AN - SCOPUS:0037380734
SN - 0026-895X
VL - 63
SP - 784
EP - 790
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 4
ER -