It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca 2+ 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 in vitro and in vivo to NMDAR-dependent Ca 2+ 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. © 2012 Elsevier Inc.
Martel, M. A., Ryan, T. J., Bell, K. F. S., Fowler, J. H., McMahon, A., Al-Mubarak, B., … Hardingham, G. E. (2012). The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults. Neuron, 74(3), 543–556. https://doi.org/10.1016/j.neuron.2012.03.021