Glutamate-induced nuclear translocation of PYK2 in hippocampal neurons, interaction with MBD2, and role in cell death in a model of epilepsy

channels, and calcineurin. NMDA receptor stimulation also increases nuclear location and interaction with PYK2 of methyl-CpG binding domain protein 2 (MBD2), a modulator of histone modifications and nucleosome remodeling. In PYK2-KO neurons, MBD2 nuclear translocation is diminished, acetylation of histone H4-Lys5 is decreased, and methylation of histone H3-Lys4 is increased. The transcriptome is modified in PYK2-KO hippocampus with a decreased expression of genes coding for excitatory synaptic proteins. In cultured neurons, the absence of PYK2 enhances the glutamate-induced downregulation of synaptic protein transcripts related to epilepsy pathophysiology. In wild-type mice, pilocarpine-induced status epilepticus increases PYK2 and MBD2 nuclear localization in hippocampal neurons, especially in CA3. In PYK2-KO mice, aberrant synaptic sprouting and cell death triggered by status epilepticus are reduced in CA3 compared to wild-type littermates. In PYK2-KO neurons in culture, glutamate-induced cell death is attenuated, and this effect is abolished by re-expression of wild-type PYK2 but not of mutated PYK2 unable to translocate to the nucleus. In summary, our study indicates that regulated PYK2 nuclear translocation in hippocampal neurons may facilitate transcription by removing MBD2 from the active chromatin and may contribute to seizure-induced neurotoxicity.

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Journal
Cell Death and Disease
Published
2026-04-22
DOI
https://doi.org/10.1038/s41419-026-08628-x
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
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article

Glutamate-induced nuclear translocation of PYK2 in hippocampal neurons, interaction with MBD2, and role in cell death in a model of epilepsy

Albert Giralt, Enrica Montalban, Marcos Galán-Ganga, Margot Chouchana et al.
Cell Death and Disease
Neuroscience and Neuropharmacology Research
article

Glutamate-induced nuclear translocation of PYK2 in hippocampal neurons, interaction with MBD2, and role in cell death in a model of epilepsy

Albert Giralt, Enrica Montalban, Marcos Galán-Ganga, Margot Chouchana, Sophie Longueville, Jean‐Antoine Girault, Carmen Cifuentes-Díaz, Tiago Mendes, Damien Carrel, Benoit de Pins
article en

Abstract

channels, and calcineurin. NMDA receptor stimulation also increases nuclear location and interaction with PYK2 of methyl-CpG binding domain protein 2 (MBD2), a modulator of histone modifications and nucleosome remodeling. In PYK2-KO neurons, MBD2 nuclear translocation is diminished, acetylation of histone H4-Lys5 is decreased, and methylation of histone H3-Lys4 is increased. The transcriptome is modified in PYK2-KO hippocampus with a decreased expression of genes coding for excitatory synaptic proteins. In cultured neurons, the absence of PYK2 enhances the glutamate-induced downregulation of synaptic protein transcripts related to epilepsy pathophysiology. In wild-type mice, pilocarpine-induced status epilepticus increases PYK2 and MBD2 nuclear localization in hippocampal neurons, especially in CA3. In PYK2-KO mice, aberrant synaptic sprouting and cell death triggered by status epilepticus are reduced in CA3 compared to wild-type littermates. In PYK2-KO neurons in culture, glutamate-induced cell death is attenuated, and this effect is abolished by re-expression of wild-type PYK2 but not of mutated PYK2 unable to translocate to the nucleus. In summary, our study indicates that regulated PYK2 nuclear translocation in hippocampal neurons may facilitate transcription by removing MBD2 from the active chromatin and may contribute to seizure-induced neurotoxicity.

Cell Death and Disease
Délégation Paris 5 (FR), Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Université Sorbonne Nouvelle (FR), Université Paris Cité (FR), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Centre d'Économie de la Sorbonne (FR), Centre National pour la Recherche Scientifique et Technique (CNRST) (MA), Sorbonne Paris Cité (FR), Departament de Salut (ES), AstraZeneca (Netherlands) (NL), Centre de Recherche Saint-Antoine (FR), AstraZeneca (Finland) (FI), Institut du Fer à Moulin (FR), Institut du Cerveau (FR), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), SPPIN - Saints-Pères Paris Institute for Neurosciences (FR), Université Paris 1 Panthéon-Sorbonne (FR), University of Naples Federico II (IT), Universitat de Barcelona (ES)
Fundación Ramón Areces, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Sorbonne Université, Agencia Estatal de Investigación
Good health and well-being
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Neuroscience and Neuropharmacology Research
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