Vol. 63, Issue 4, 784-790, April 2003

Nuclear Translocation of Nuclear Transcription Factor-B by -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors Leads to Transcription of p53 and Cell Death in Dopaminergic Neurons

Gabriel A. de Erausquin, Krzyztof Hyrc, David A. Dorsey, Daniel Mamah, Mehmet Dokucu, Daniel H. Mascó, Timothy Walton, Krikor Dikranian, Mario Soriano, José Manuel García Verdugo, Mark P. Goldberg, and Laura L. Dugan

Departments of Psychiatry (G.A.d.E., D.A.D., D.M., M.D., K.D.) and Neurology (G.A.d.E., T.W., M.P.G., L.L.D.) and Center for the Study of Nervous System Injury (G.A.d.E., K.H., M.P.G., L.L.D.), Washington University School of Medicine, St. Louis, Missouri; Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina (D.H.M.); and Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain (M.S., J.M.G.V.)

We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor B (NFB) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with -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 NFB, 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.