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 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

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 Komiyama, Karen Horsburgh, Peter C Kind, Seth G N Grant, David J A Wyllie, Giles E Hardingham

Research output: Contribution to journal › Article › peer-review

Abstract

It 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 (CTD^2B) and GluN2A (CTD^2A). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD^2B enhances NMDAR toxicity, compared to CTD^2A. Furthermore, the vulnerability of forebrain neurons invitro and invivo 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, CTD^2B 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.

Original language	English
Pages (from-to)	543-556
Number of pages	14
Journal	Neuron
Volume	74
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2012.03.021
Publication status	Published - May 2012

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10.1016/j.neuron.2012.03.021

The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults
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http://www.cell.com/neuron/retrieve/pii/S0896627312002899

FELLOWSHIP: Control of neuroprotection through NMDA receptor dependant regulation of antioxidant status.
Hardingham, G.
MRC
1/10/10 → 30/11/17
Project: Research
The cellular basis of FMRP function
Kind, P. & Wyllie, D.
MRC
1/05/08 → 30/04/12
Project: Research
The roles of FMRP in cortical development
Kind, P.
MRC
1/07/07 → 30/06/10
Project: Research

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@article{6b56b1ba1aea4ec78040338b7fd8433c,

title = "The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults",

abstract = "It 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 invitro and invivo 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. ",

author = "Marc-Andr{\'e} Martel and Ryan, {Tom{\'a}s J} and Bell, {Karen F S} and Fowler, {Jill H} and Aoife McMahon and Bashayer Al-Mubarak and Noboru Komiyama and Karen Horsburgh and Kind, {Peter C} and Grant, {Seth G N} and Wyllie, {David J A} and Hardingham, {Giles E}",

year = "2012",

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T1 - The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults

AU - Martel, Marc-André

AU - Ryan, Tomás J

AU - Bell, Karen F S

AU - Fowler, Jill H

AU - McMahon, Aoife

AU - Al-Mubarak, Bashayer

AU - Komiyama, Noboru

AU - Horsburgh, Karen

AU - Kind, Peter C

AU - Grant, Seth G N

AU - Wyllie, David J A

AU - Hardingham, Giles E

PY - 2012/5

Y1 - 2012/5

N2 - It 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 invitro and invivo 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.

AB - It 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 invitro and invivo 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.

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DO - 10.1016/j.neuron.2012.03.021

M3 - Article

C2 - 22578505

SN - 1097-4199

VL - 74

SP - 543

EP - 556

JO - Neuron

JF - Neuron

IS - 3

ER -

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

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FELLOWSHIP: Control of neuroprotection through NMDA receptor dependant regulation of antioxidant status.

The cellular basis of FMRP function

The roles of FMRP in cortical development

Cite this