title: Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons.
abstract: The activation of N-Methyl D-Aspartate Receptor (NMDAR) by glutamate is crucial in the nervous system function, particularly in memory and learning. NMDAR is composed by two GluN1 and two GluN2 subunits. GluN2B has been reported to participate in the prevalent NMDAR subtype at synapses, the GluN1/2A/2B. Here we studied the regulation of GluN2B expression in cortical neurons finding that glutamate up-regulates GluN2B translation through the action of nitric oxide (NO), which induces the phosphorylation of the eukaryotic translation initiation factor 2 α (eIF2α). It is a process mediated by the NO-heme-regulated eIF2α kinase (HRI), as the effect was avoided when a specific HRI inhibitor or a HRI small interfering RNA (siHRI) were used. We found that the expressed GluN2B co-localizes with PSD-95 at the postsynaptic ending, which strengthen the physiological relevance of the proposed mechanism. Moreover the receptors bearing GluN2B subunits upon NO stimulation are functional as high Ca2+ entry was measured and increases the co-localization between GluN2B and GluN1 subunits. In addition, the injection of the specific HRI inhibitor in mice produces a decrease in memory retrieval as tested by the Novel Object Recognition performance. Summarizing our data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons.
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramos-Fernández
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Tajes
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Ill-Raga
authors.affiliation: Cell Signaling Laboratory, Department of Cellular and Molecular Biology, Faculty of Biological Science, Pontificia Universidad Católica, Santiago, Chile.
authors.forename: Lina
authors.initials: L
authors.lastname: Vargas
authors.affiliation: Neuropharmacology Laboratory, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Busquets-García
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Bosch-Morató
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Biuse
authors.initials: B
authors.lastname: Guivernau
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Valls-Comamala
authors.affiliation: Neuropharmacology Laboratory, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Gomis
authors.affiliation: Bellvitge Biomedical Research Institute, Unit of Neuropharmacology and Pain, University of Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Grau
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Fandos
authors.affiliation: Janssen Research and Development, L.L.C., San Diego, CA, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rosen
authors.affiliation: Janssen Research and Development, L.L.C., San Diego, CA, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Rabinowitz
authors.affiliation: CARE, Department of Cellular and Molecular Biology, Faculty of Biological Science, Pontificia Universidad Católica, Santiago, Chile.
authors.forename: Nibaldo
authors.initials: N
authors.lastname: Inestrosa
authors.affiliation: Neuropharmacology Laboratory, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Bellvitge Biomedical Research Institute, Unit of Neuropharmacology and Pain, University of Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Altafaj
authors.affiliation: Neuropharmacology Laboratory, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Ozaita
authors.affiliation: Cell Signaling Laboratory, Department of Cellular and Molecular Biology, Faculty of Biological Science, Pontificia Universidad Católica, Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Alvarez
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Vicente
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000473:pathology*; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D018683:Excitatory Amino Acid Agents / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006801:Humans; D008568:Memory; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; D015852:Eukaryotic Initiation Factor-2; D018683:Excitatory Amino Acid Agents; C121001:NR2B NMDA receptor; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D006418:Heme
keywords: GluN2B; HRI kinase; nitric oxide; synapse; translation; Neuroscience