MST1 mediates the N-methyl-d-aspartate-induced excitotoxicity in mouse cortical neurons

Jane Melissa Lim, Rumi Lee, Yeonsil Kim, In Young Lee, Eunju Kim, Eui Ju Choi

    Research output: Contribution to journalArticlepeer-review

    1 Citation (Scopus)

    Abstract

    Excessive activation of the ionotropic N-methyl-d-aspartate (NMDA) receptor has been shown to cause abnormally high levels of Ca2+ influx, thereby leading to excitotoxic neuronal death. In this study, exposure of mouse primary cortical neurons to NMDA resulted in the cleavage and activation of mammalian sterile 20-like kinase-1 (MST1), both of which were mediated by calpain 1. In vitro cleavage assay data indicated that calpain 1 cleaves out the autoinhibitory domain of MST1 to generate an active form of the kinase. Furthermore, calpain 1 mediated the cleavage and activation of wild-type MST1, but not of MST1 (G339A). Intriguingly, NMDA/calpain-induced MST1 activation promoted the nuclear translocation of the kinase and the phosphorylation of histone H2B in mouse cortical neurons, leading to excitotoxicity. Thus, we propose a previously unrecognized mechanism of MST1 activation associated with NMDA-induced excitotoxic neuronal death.

    Original languageEnglish
    Article number15
    JournalCellular and Molecular Life Sciences
    Volume79
    Issue number1
    DOIs
    Publication statusPublished - 2022 Jan

    Bibliographical note

    Funding Information:
    This work was supported by a NRF Grant (NRF-2020R1A2C2011392) funded by the Ministry of Science and ICT of Korea as well as by a Korea University grant (E.-J.C.).

    Publisher Copyright:
    © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

    Keywords

    • Calcium-dependent cleavage
    • Glutamate receptor
    • Histone H2B
    • Neurotoxicity
    • Protein kinase

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Pharmacology
    • Cellular and Molecular Neuroscience
    • Cell Biology

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