Nuclear translocation of nuclear transcription factor-kappa B by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons.
We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor kappa B (NF kappa B) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with alpha-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 NF kappa B, 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.
de Erausquin
Gabriel A
GA
Department of Psychiatry and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA. erausquing@neuro.wustl.edu
Hyrc
Krzyztof
K
Dorsey
David A
DA
Mamah
Daniel
D
Dokucu
Mehmet
M
Mascó
Daniel H
DH
Walton
Timothy
T
Dikranian
Krikor
K
Soriano
Mario
M
García Verdugo
José Manuel
JM
Goldberg
Mark P
MP
Dugan
Laura L
LL
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002463:Cell Membrane Permeability / Q000187:drug effects; D005260:Female; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology*; D011954:Receptors, Dopamine / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D016328:NF-kappa B; D018091:Receptors, AMPA; D011954:Receptors, Dopamine; D016159:Tumor Suppressor Protein p53; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002118:Calcium