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

Overview

Authors: Albert Giralt1,2,3,4,5,6,7, Tiago Mendes1,2,3,8, Enrica Montalban1,2,3,9, Carmen Cifuentes-Diaz1,2,3, Marcos Galán-Ganga4,5,6, Margot Chouchana1,2,3,10, Benoît de Pins1,2,3,11, Sophie Longueville1,2,3, Damien Carrel1,2,3,12, Jean-Antoine Girault1,2,3,13
ORCID iDs: Albert Giralt, Tiago Mendes, Marcos Galán-Ganga, Benoît de Pins, Damien Carrel, Jean-Antoine Girault
13 affiliations
  1. Inserm UMR-S 1270, Paris, France
  2. Sorbonne Université, Faculté des Sciences et d’Ingénierie, Paris, France
  3. Institut du Fer à Moulin, Paris, France
  4. Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain
  5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
  6. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  7. Production and Validation Center of Advanced Therapies (Creatio), University of Barcelona, Barcelona, Spain
  8. Present Address: Astrazeneka, Göteborg, Sweden
  9. Present Address: Université de Bordeaux, INRAE, UMR 1286, Bordeaux, France
  10. Present Address: Université Paris Cité, Inserm, UMRS-1144, Faculté de pharmacie de Paris, Paris, France
  11. Present Address: Department of Biology, University of Naples “Federico II”, Naples, Italy
  12. Present Address: Université de Paris, Centre National de la Recherche Scientifi que (CNRS), UMR 8003, Paris, France
  13. Present Address: Institut du Cerveau (ICM), Paris Brain Institute, Inserm, CNRS, Sorbonne Université, Paris, France
Institutions: Inserm (France); Sorbonne Université (France); Biomedical Research Networking Center on Neurodegenerative Diseases (Spain); Centro de Investigación Biomédica en Red (Spain); Institut du Fer à Moulin (France); Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (Spain); Universitat de Barcelona (Spain); AstraZeneca (Sweden) (Sweden); Université de Bordeaux (France); Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (France); NutriNeuro (France); Université Paris Cité (France); Optimisation Thérapeutique en Neuropsychopharmacologie (France); University of Naples Federico II (Italy); Centre National de la Recherche Scientifique (France); SPPIN - Saints-Pères Paris Institute for Neurosciences (France); Institut du Cerveau (France)
Journal: Cell death & disease, volume 17, issue 1, article 535
Dates: received 16 June 2025; accepted 9 March 2026; published online 22 April 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41419-026-08628-x · PMID 42020370 · PMCID PMC13237024 · OpenAlex W7155198816
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), epilepsy (population), cellular / molecular (subfield)
Methods: Evoked potentials
Keywords: Cell death in the nervous system, Mechanisms of disease
MeSH: Cell Nucleus*, DNA-Binding Proteins*, Epilepsy*, Glutamic Acid*, Hippocampus*, Neurons*, Active Transport, Cell Nucleus, Animals, Cell Death, Cells, Cultured, Disease Models, Animal, Histones, Mice, Mice, Knockout, Protein Transport, Receptors, N-Methyl-D-Aspartate (* major topic)
Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Fondation pour la Recherche Médicale (Foundation for Medical Research in France) (FDT201805005390, EQU201903007844); Agence Nationale de la Recherche (French National Research Agency) (ANR-19-CE16-0020)
Citations: cited by 1 paper (Europe PMC); 66 references in the paper

Abstract

Synaptic activity results in long-lasting alterations of neuronal properties, which require gene expression regulation. PYK2 is a calcium-activated non-receptor protein tyrosine kinase highly expressed in hippocampal neurons and involved in synaptic functions. PYK2 also shuttles between the nucleus and the cytoplasm. We show that glutamate stimulation induces PYK2 accumulation in the nucleus of hippocampal neurons in culture through activation of NMDA receptors, L-type voltage-gated Ca2+ 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data can be available on demand. Sequencing data are available at https://www.ncbi.nlm.nih.gov/geo (pending).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 2 keywords, 16 MeSH terms, 2 funders, 65 references.

Cite

This paper

Giralt, A., Mendes, T., Montalban, E., Cifuentes-Diaz, C., Galán-Ganga, M., Chouchana, M., de Pins, B., Longueville, S., Carrel, D., & Girault, J.-A. (2026). Glutamate-induced nuclear translocation of PYK2 in hippocampal neurons, interaction with MBD2, and role in cell death in a model of epilepsy. Cell death & disease, 17(1), 535. https://doi.org/10.1038/s41419-026-08628-x

BibTeX

@article{giralt2026glutamate,
author = {Giralt, Albert and Mendes, Tiago and Montalban, Enrica and Cifuentes-Diaz, Carmen and Galán-Ganga, Marcos and Chouchana, Margot and de Pins, Benoît and Longueville, Sophie and Carrel, Damien and Girault, Jean-Antoine},
title = {{Glutamate-induced nuclear translocation of PYK2 in hippocampal neurons, interaction with MBD2, and role in cell death in a model of epilepsy}},
journal = {Cell death \& disease},
year = {2026},
month = apr,
volume = {17},
number = {1},
pages = {535},
publisher = {Nature Publishing Group},
issn = {2041-4889},
doi = {10.1038/s41419-026-08628-x},
url = {https://doi.org/10.1038/s41419-026-08628-x},
pmid = {42020370},
pmcid = {PMC13237024}
}

RIS

TY - JOUR
AU - Giralt, Albert
AU - Mendes, Tiago
AU - Montalban, Enrica
AU - Cifuentes-Diaz, Carmen
AU - Galán-Ganga, Marcos
AU - Chouchana, Margot
AU - de Pins, Benoît
AU - Longueville, Sophie
AU - Carrel, Damien
AU - Girault, Jean-Antoine
TI - Glutamate-induced nuclear translocation of PYK2 in hippocampal neurons, interaction with MBD2, and role in cell death in a model of epilepsy
T2 - Cell death & disease
J2 - Cell Death Dis
PY - 2026
DA - 2026/04/22
VL - 17
IS - 1
SP - 535
SN - 2041-4889
PB - Nature Publishing Group
DO - 10.1038/s41419-026-08628-x
UR - https://doi.org/10.1038/s41419-026-08628-x
LA - en
ER -

CSL-JSON

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