N-methyl-D-aspartate blocks activation of JNK and mitochondrial apoptotic pathway induced by potassium deprivation in cerebellar granule cells

Xavier Xifró, Anthony Falluel-Morel, Alfredo Miñano, Nicolas Aubert, Rut Fadó, Cristina Malagelada, David Vaudry, Hubert Vaudry, Bruno Gonzalez, José Rodríguez-Alvarez

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25 Citations (Scopus)

Abstract

During the postnatal development of cerebellum, lack of excitatory innervation from the mossy fibers results in cerebellar granule cell (CGC) apoptosis during the migration of the cells toward the internal granule cell layer. Accordingly, CGCs die by apoptosis when cultured in physiological KCl concentrations (5 mM; K5), and they survive in the presence of depolarizing conditions such as high KCl concentration (25 mM; K25) or N-methyl-D-aspartate (NMDA). We have recently shown that NMDA is able to exert a long lasting neuroprotective effect when added to immature (2 days in vitro) CGC cultures by inhibition of caspase-3 activity. Here we show that NMDA- and K25-mediated neuroprotection is associated with an increase in the levels of Bcl-2, an inhibition of K5-mediated increase in Bax, and the inhibition of the release of apoptogenic factors from mitochondria such as Smac/DIABLO and cytochrome c. Moreover, we have shown that similar effects are observed when c-Jun N-terminal kinases (JNKs) are inhibited and that treatment of CGC cultures with NMDA blocks K5-mediated JNK activation. These results allow us to postulate that the inhibition of JNK-mediated release of apoptogenic factors from mitochondria is involved in the NMDA protection from K5-mediated apoptosis of CGCs. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)6801-6812
JournalJournal of Biological Chemistry
Volume281
DOIs
Publication statusPublished - 10 Mar 2006

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    Xifró, X., Falluel-Morel, A., Miñano, A., Aubert, N., Fadó, R., Malagelada, C., Vaudry, D., Vaudry, H., Gonzalez, B., & Rodríguez-Alvarez, J. (2006). N-methyl-D-aspartate blocks activation of JNK and mitochondrial apoptotic pathway induced by potassium deprivation in cerebellar granule cells. Journal of Biological Chemistry, 281, 6801-6812. https://doi.org/10.1074/jbc.M504571200