Oncotarget

Research Papers: Neuroscience:

Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons

Eva Ramos-Fernández, Marta Tajes, Gerard ILL-Raga, Lina Vargas, Arnau Busquets-García, Mònica Bosch-Morató, Biuse Guivernau, Victòria Valls-Comamala, Maria Gomis, Cristina Grau, César Fandos, Mark D. Rosen, Michael H. Rabinowitz, Nibaldo Inestrosa, Rafael Maldonado, Xavier Altafaj, Andrés Ozaita, Alejandra Alvarez, Rubén Vicente, Miguel A. Valverde and Francisco J. Muñoz _

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Oncotarget. 2016; 7:58876-58892. https://doi.org/10.18632/oncotarget.11417

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Abstract

Eva Ramos-Fernández1,*, Marta Tajes1,*, Gerard ILL-Raga1, Lina Vargas2, Arnau Busquets-García3, Mònica Bosch-Morató1, Biuse Guivernau1, Victòria Valls-Comamala1, Maria Gomis3, Cristina Grau6, César Fandos1, Mark D. Rosen4, Michael H. Rabinowitz4, Nibaldo Inestrosa5, Rafael Maldonado3, Xavier Altafaj6, Andrés Ozaita3, Alejandra Alvarez2, Rubén Vicente1, Miguel A. Valverde1 and Francisco J. Muñoz1

1 Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain

2 Cell Signaling Laboratory, Department of Cellular and Molecular Biology, Faculty of Biological Science, Pontificia Universidad Católica, Santiago, Chile

3 Neuropharmacology Laboratory, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain

4 Janssen Research and Development, L.L.C., San Diego, CA, United States of America

5 CARE, Department of Cellular and Molecular Biology, Faculty of Biological Science, Pontificia Universidad Católica, Santiago, Chile

6 Bellvitge Biomedical Research Institute, Unit of Neuropharmacology and Pain, University of Barcelona, Barcelona, Spain

* These authors have contributed equally to the present work

Correspondence to:

Francisco J. Muñoz, email:

Keywords: GluN2B, HRI kinase, nitric oxide, synapse, translation, Neuroscience

Received: February 24, 2016 Accepted: August 13, 2016 Published: August 19, 2016

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.


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