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 language | English |
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Article number | 15 |
Journal | Cellular and Molecular Life Sciences |
Volume | 79 |
Issue number | 1 |
DOIs | |
Publication status | Published - 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