title: Identification of NADPH oxidase as a key mediator in the post-ischemia-induced sequestration and degradation of the GluA2 AMPA receptor subunit.
abstract: A hallmark of ischemic/reperfusion injury is a change in subunit composition of synaptic 2-amino-3-(3-hydroxy-5-methylisoazol-4-yl)propionic acid receptors (AMPARs). This change in AMPAR subunit composition leads to an increase in surface expression of GluA2-lacking Ca(2+) /Zn(2+) permeable AMPARs. These GluA2-lacking AMPARs play a key role in promoting delayed neuronal death following ischemic injury. At present, the mechanism(s) responsible for the ischemia/reperfusion-induced subunit composition switch and degradation of the GluA2 subunit remain unclear. In this study, we investigated the role of NADPH oxidase, and its importance in mediating endocytosis and subsequent degradation of the GluA2 AMPAR subunit in adult rat hippocampal slices subjected to oxygen-glucose deprivation/reperfusion (OGD/R) injury. In hippocampal slices pre-treated with the NADPH oxidase inhibitor apocynin attenuated OGD/R-mediated sequestration of GluA2 and GluA1 as well as prevent the degradation of GluA2. We provide compelling evidence that NADPH oxidase mediated sequestration of GluA1- and GluA2- involved activation of p38 MAPK. Furthermore, we demonstrate that inhibition of NADPH oxidase blunts the OGD/R-induced association of GluA2 with protein interacting with C kinase-1. In summary, this study identifies a novel mechanism that may underlie the ischemia/reperfusion-induced AMPAR subunit composition switch and a potential therapeutic target.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences and the Center for Structural and Functional Neuroscience, The University of Montana, Missoula, Montana, USA.
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Beske
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences and the Center for Structural and Functional Neuroscience, The University of Montana, Missoula, Montana, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Byrnes
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences and the Center for Structural and Functional Neuroscience, The University of Montana, Missoula, Montana, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Astruc-Diaz
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences and the Center for Structural and Functional Neuroscience, The University of Montana, Missoula, Montana, USA.
authors.forename: Darrell A
authors.initials: DA
authors.lastname: Jackson
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: D018091:Receptors, AMPA; D019255:NADPH Oxidases; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPA receptor; GluA2; NADPH oxidase; ischemia; p38 MAPK