The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults

Marc-André Martel,Tomás J Ryan,Karen F.S Bell,Jill H Fowler,Aoife Mcmahon,Bashayer Al-Mubarak,Noboru H Komiyama,Karen Horsburgh,Peter C Kind,Seth G.N Grant,David J.A Wyllie,Giles E Hardingham

doi:10.1016/j.neuron.2012.03.021

Marc-André Martel, Tomás J Ryan + Show 10 more

Open Access

https://doi.org/10.1016/j.neuron.2012.03.021

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Journal: Neuron	Publication Date: May 1, 2012
Citations: 221	License type: cc-by

Affiliation: University of Edinburgh, University of Cambridge

Abstract

SummaryIt is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca2+ influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD2B) and GluN2A (CTD2A). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD2B enhances NMDAR toxicity, compared to CTD2A. Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca2+ influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD2B exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity.

Highlights

Sustained elevated levels of extracellular glutamate kill central neurons (Olney, 1969)
By studying signaling from wildtype and chimeric GluN2A/2B subunits, using both acutely expressed subunits as well as a mouse knockin model, we find that the presence of the C-terminal domains of GluN2B (CTD2B) in an NMDA subtype of glutamate receptor (NMDAR) renders Ca2+ influx through this receptor more toxic than the presence of CTD2A
We created constructs encoding chimeric receptors based on GluN2B and GluN2A but with their respective C-terminal domains (CTDs) replaced with each other’s (GluN2B2A(CTR) and GluN2A2B(CTR), respectively, Figure 1A)

Summary

Introduction

Sustained elevated levels of extracellular glutamate kill central neurons (Olney, 1969). GluN2 subunits have large, evolutionarily divergent cytoplasmic C-terminal domains (CTDs), which have the potential to differentially associate with signaling molecules (Ryan et al, 2008). This compositional diversity raises the (unresolved) question as to whether the GluN2 subtype (GluN2A versus GluN2B) differentially influences the toxicity of Ca2+ influx through NMDARs. There is evidence that GluN2Band GluN2A-containing NMDARs are both capable of mediating excitotoxicity (Graham et al, 1992; Lau and Tymianski, 2010; von Engelhardt et al, 2007); whether they do so with differing efficiency or mechanisms is unclear

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