6533b82cfe1ef96bd1290129

RESEARCH PRODUCT

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

Krikor DikranianGabriel A. De ErausquinKrzyztof HyrcTim WaltonDaniel H. MascóMario SorianoDaniel MamahLaura L. DuganMehmet E. DokucuMark P. GoldbergJosé Manuel García VerdugoDavid A. Dorsey

subject

Programmed cell deathCell Membrane PermeabilityTime FactorsCIENCIAS MÉDICAS Y DE LA SALUDTranscription GeneticNeuriteActive Transport Cell NucleusInmunologíaExcitotoxicitymedicine.disease_causeCELL DEATHReceptors DopamineRats Sprague-DawleymedicineAnimalsReceptors AMPAalpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic AcidTranscription factorPARKINSON DISEASECaspaseNeuronsPharmacologyCell DeathNUCLEAR TRANSCRIPTIONbiologyDopaminergicNF-kappa BNFKB1Molecular biologyMitochondriaRatsCell biologyMedicina Básicabiology.proteinMolecular MedicineCalciumFemaleTumor Suppressor Protein p53Signal transduction

description

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. Fil: de Erausquin, Gabriel Alejandro. Washington University School of Medicine; Estados Unidos Fil: Hyrc, Krzyztof. Washington University School of Medicine; Estados Unidos Fil: Dorsey, David A.. Washington University School of Medicine; Estados Unidos Fil: Mamah, Daniel. Washington University School of Medicine; Estados Unidos Fil: Dokucu, Mehmet. Washington University School of Medicine; Estados Unidos Fil: Masco, Daniel Hugo. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Walton, Timothy. Washington University School of Medicine; Estados Unidos Fil: Dikranian, Krikor. Washington University School of Medicine; Estados Unidos Fil: Soriano, Mario. Universidad de Valencia; España Fil: Garcia Verdugo, José Manuel. Universidad de Valencia; España Fil: Goldberg, Mark P.. Washington University School of Medicine; Estados Unidos Fil: Dugan, Laura L.. Washington University School of Medicine; Estados Unidos

yearjournalcountryeditionlanguage
2003-04-01Molecular Pharmacology
https://doi.org/10.1124/mol.63.4.784