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

• Published in: Molecular pharmacology 2003-04, Vol.63 (4), p.784
• Main Authors: Gabriel A. de Erausquin, Krzyztof Hyrc, David A. Dorsey, Daniel Mamah, Mehmet Dokucu, Daniel H. MascÃ, Timothy Walton, Krikor Dikranian, Mario Soriano, José Manuel Garcı́a Verdugo, Mark P. Goldberg, Laura L. Dugan
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.63.4.784

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 Ca 2+ 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.