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Research ArticleArticle

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

Gabriel A. de Erausquin, Krzyztof Hyrc, David A. Dorsey, Daniel Mamah, Mehmet Dokucu, Daniel H. Mascó, Timothy Walton, Krikor Dikranian, Mario Soriano, José Manuel Garcı́a Verdugo, Mark P. Goldberg and Laura L. Dugan
Molecular Pharmacology April 2003, 63 (4) 784-790; DOI: https://doi.org/10.1124/mol.63.4.784
Gabriel A. de Erausquin
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Krzyztof Hyrc
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David A. Dorsey
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Daniel Mamah
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Mehmet Dokucu
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Daniel H. Mascó
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Timothy Walton
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Krikor Dikranian
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Mario Soriano
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José Manuel Garcı́a Verdugo
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Mark P. Goldberg
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Laura L. Dugan
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Abstract

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 oncogenep53. 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.

Footnotes

  • This work was partially supported by National Institutes of Health grants (to M.P.G. and L.L.D.) and by a Joint Junior Faculty Award of the United Parkinson Foundation and the Parkinson Disease Foundation (to G.A.d.E.).

  • Abbreviations:
    PD
    Parkinson disease
    DN
    dopaminergic neuron
    TNF
    tumor necrosis factor
    NFκB
    nuclear transcription factor κB
    GluR
    glutamate receptor
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    ROS
    reactive oxygen species
    TH
    tyrosine hydroxylase
    phos-p53
    phosphoprotein p53
    MAP2
    microtubule associated protein 2
    EM
    electron microscopy
    5,7-DHT
    5,7-dihydroxitryptamine
    DHR123
    dihydrorhodamine 123
    DTT
    dithiothreitol
    PMSF
    phenylmethylsulfonyl fluoride
    EMSA
    electrophoretic mobility shift assay
    ELISA
    enzyme-linked immunosorbent assay
    PCR
    polymerase chain reaction
    NBQX
    1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide
    NAS
    1-napthyl-acetyl spermine trihydrochloride
    CSA
    cyclosporin A
    DEA/NO
    sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate
    PDTC
    pyrrolidine dithiocarbamate
    LTCC
    L-type Ca2+channel
    Cyt-c
    cytochrome c
    mPT
    mitochondrial permeability transition
    NO
    nitric oxide NOS, nitric-oxide synthase
    • Received October 22, 2002.
    • Accepted December 20, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (4)
Molecular Pharmacology
Vol. 63, Issue 4
1 Apr 2003
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Research ArticleArticle

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

Gabriel A. de Erausquin, Krzyztof Hyrc, David A. Dorsey, Daniel Mamah, Mehmet Dokucu, Daniel H. Mascó, Timothy Walton, Krikor Dikranian, Mario Soriano, José Manuel Garcı́a Verdugo, Mark P. Goldberg and Laura L. Dugan
Molecular Pharmacology April 1, 2003, 63 (4) 784-790; DOI: https://doi.org/10.1124/mol.63.4.784

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Research ArticleArticle

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

Gabriel A. de Erausquin, Krzyztof Hyrc, David A. Dorsey, Daniel Mamah, Mehmet Dokucu, Daniel H. Mascó, Timothy Walton, Krikor Dikranian, Mario Soriano, José Manuel Garcı́a Verdugo, Mark P. Goldberg and Laura L. Dugan
Molecular Pharmacology April 1, 2003, 63 (4) 784-790; DOI: https://doi.org/10.1124/mol.63.4.784
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