title: Direct interaction between GluR2 and GAPDH regulates AMPAR-mediated excitotoxicity.
abstract: Over-activation of AMPARs (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors) is implicated in excitotoxic neuronal death associated with acute brain insults, such as ischemic stroke. However, the specific molecular mechanism by which AMPARs, especially the calcium-impermeable AMPARs, induce neuronal death remains poorly understood. Here we report the identification of a previously unrecognized molecular pathway involving a direct protein-protein interaction that underlies GluR2-containing AMPAR-mediated excitotoxicity. Agonist stimulation of AMPARs promotes GluR2/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) complex formation and subsequent internalization. Disruption of GluR2/GAPDH interaction by administration of an interfering peptide prevents AMPAR-mediated excitotoxicity and protects against damage induced by oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia.
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Shupeng
authors.initials: S
authors.lastname: Li
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Pei
authors.forename: Shengwei
authors.initials: S
authors.lastname: Zou
authors.forename: Frank J S
authors.initials: FJ
authors.lastname: Lee
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D014162:Transfection
chemical_list: D009498:Neurotoxins; D021122:Protein Subunits; D018091:Receptors, AMPA; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D005947:Glucose; C104722:glutamate receptor ionotropic, AMPA 2; D010100:Oxygen