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 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.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Martel
authors.forename: Tomás J
authors.initials: TJ
authors.lastname: Ryan
authors.forename: Karen F S
authors.initials: KF
authors.lastname: Bell
authors.forename: Jill H
authors.initials: JH
authors.lastname: Fowler
authors.forename: Aoife
authors.initials: A
authors.lastname: McMahon
authors.forename: Bashayer
authors.initials: B
authors.lastname: Al-Mubarak
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.forename: Karen
authors.initials: K
authors.lastname: Horsburgh
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D002118:Calcium; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; D008565:Membrane Proteins; D016202:N-Methylaspartate; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; C501447:Dlg4 protein, mouse; C121001:NR2B NMDA receptor