Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to neuronal death following in vitro ischemia.

Marta M. Vieira, Jeannette Schmidt, Joana S. Ferreira, Kevin She, Shinichiro Oku, Miranda Mele, Armanda E. Santos, Carlos B. Duarte, Ann Marie Craig, Ana Luísa Carvalho
Neurobiology of Disease. 2016-05-01; 89: 223-234
DOI: 10.1016/j.nbd.2015.11.007

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1. Neurobiol Dis. 2016 May;89:223-34. doi: 10.1016/j.nbd.2015.11.007. Epub 2015 Nov
12.

Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to
neuronal death following in vitro ischemia.

Vieira MM(1), Schmidt J(2), Ferreira JS(1), She K(3), Oku S(3), Mele M(1), Santos
AE(4), Duarte CB(5), Craig AM(3), Carvalho AL(6).

Author information:
(1)CNC – Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal.
(2)CNC – Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal; PDBEB – Doctoral Program in Experimental Biology and
Biomedicine, Center for Neuroscience and Cell Biology, Institute for
Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
(3)Brain Research Centre and Department of Psychiatry, University of British
Columbia, Vancouver, BC, Canada.
(4)CNC – Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
(5)CNC – Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra,
Portugal.
(6)CNC – Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra,
Portugal. Electronic address: .

Global cerebral ischemia induces selective degeneration of specific subsets of
neurons throughout the brain, particularly in the hippocampus and cortex. One of
the major hallmarks of cerebral ischemia is excitotoxicity, characterized by
overactivation of glutamate receptors leading to intracellular Ca(2+) overload
and ultimately neuronal demise. N-methyl-d-aspartate receptors (NMDARs) are
considered to be largely responsible for excitotoxic injury due to their high
Ca(2+) permeability. In the hippocampus and cortex, these receptors are most
prominently composed of combinations of two GluN1 subunits and two GluN2A and/or
GluN2B subunits. Due to the controversy regarding the differential role of GluN2A
and GluN2B subunits in excitotoxic cell death, we investigated the role of GluN2B
in the activation of pro-death signaling following an in vitro model of global
ischemia, oxygen and glucose deprivation (OGD). For this purpose, we used
GluN2B(-/-) mouse cortical cultures and observed that OGD-induced damage was
reduced in these neurons, and partially prevented in wild-type rat neurons by a
selective GluN2B antagonist. Notably, we found a crucial role of the C-terminal
domain of the GluN2B subunit in triggering excitotoxic signaling. Indeed,
expression of YFP-GluN2B C-terminus mutants for the binding sites to
post-synaptic density protein 95 (PSD95), Ca(2+)-calmodulin kinase IIα (CaMKIIα)
or clathrin adaptor protein 2 (AP2) failed to mediate neuronal death in OGD
conditions. We focused on the GluN2B-CaMKIIα interaction and found a determinant
role of this interaction in OGD-induced death. Inhibition or knock-down of
CaMKIIα exerted a neuroprotective effect against OGD-induced death, whereas
overexpression of this kinase had a detrimental effect. Importantly, in
comparison with neurons overexpressing wild-type CaMKIIα, neurons overexpressing
a mutant form of the kinase (CaMKII-I205K), unable to interact with GluN2B, were
partially protected against OGD-induced damage. Taken together, our results
identify crucial determinants in the C-terminal domain of GluN2B subunits in
promoting neuronal death in ischemic conditions. These mechanisms underlie the
divergent roles of the GluN2A- and GluN2B-NMDARs in determining neuronal fate in
cerebral ischemia.

Copyright © 2015 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.nbd.2015.11.007
PMID: 26581639 [Indexed for MEDLINE]


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