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

• Published in: Neuron (Cambridge, Mass.) Vol. 74; no. 3; pp. 543 - 556
• Main Authors: Martel, Marc-André, Ryan, Tomás J., Bell, Karen F.S., Fowler, Jill H., McMahon, Aoife, Al-Mubarak, Bashayer, Komiyama, Noboru H., Horsburgh, Karen, Kind, Peter C., Grant, Seth G.N., Wyllie, David J.A., Hardingham, Giles E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.05.2012; Elsevier Limited; Cell Press
• Subjects: Animals; Apoptosis; Calcium - metabolism; Calcium influx; Cells, Cultured; Cyclic AMP response element-binding protein; Disks Large Homolog 4 Protein; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation; Embryo, Mammalian; Excitotoxicity; Exons; Forebrain; Gene expression; Glial Fibrillary Acidic Protein - metabolism; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Green Fluorescent Proteins - genetics; Guanylate Kinases - metabolism; Hippocampus - cytology; Membrane Potentials - drug effects; Membrane Potentials - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Models, Biological; N-Methyl-D-aspartic acid receptors; N-Methylaspartate - pharmacology; Neurons; Neurons - drug effects; Neurons - physiology; Neurotoxins - pharmacology; Patch-Clamp Techniques; Protein Structure, Tertiary - genetics; Protein Structure, Tertiary - physiology; Rats; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Scholarships & fellowships; Toxicity; Transfection
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2012.03.021

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 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. ► The CTD of GluN2B promotes excitotoxicity better than that of GluN2A ► GluN2 CTD subtype differences are seen in both WT and chimeric 2A/2B subunits ► The GluN2B CTD couples to a prodeath PSD-95/nNOS-dependent CREB shut-off pathway Martel et al. find that the two subtypes (2A versus 2B) of the GluN2 C-terminal domain differentially couple to the CREB shut-off pathway, causing distinct effects on NMDA receptor-mediated neuronal death both in vitro and in vivo.