Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons.
Oncotarget. 2016-08-19; 7(37):
DOI: 10.18632/oncotarget.11417
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1. Oncotarget. 2016 Sep 13;7(37):58876-58892. doi: 10.18632/oncotarget.11417.
Glutamatergic stimulation induces GluN2B translation by the nitric
oxide-Heme-Regulated eIF2α kinase in cortical neurons.
Ramos-Fernández E(1), Tajes M(1), Ill-Raga G(1), Vargas L(2), Busquets-García
A(3), Bosch-Morató M(1), Guivernau B(1), Valls-Comamala V(1), Gomis M(3), Grau
C(4), Fandos C(1), Rosen MD(5), Rabinowitz MH(5), Inestrosa N(6), Maldonado R(3),
Altafaj X(4), Ozaita A(3), Alvarez A(2), Vicente R(1), Valverde MA(1), Muñoz
FJ(1).
Author information:
(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)Bellvitge Biomedical Research Institute, Unit of Neuropharmacology and Pain,
University of Barcelona, Barcelona, Spain.
(5)Janssen Research and Development, L.L.C., San Diego, CA, United States of
America.
(6)CARE, Department of Cellular and Molecular Biology, Faculty of Biological
Science, Pontificia Universidad Católica, Santiago, Chile.
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.
DOI: 10.18632/oncotarget.11417
PMCID: PMC5312282
PMID: 27557499 [Indexed for MEDLINE]