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Identification of NADPH oxidase as a key mediator in the post‐ischemia‐induced sequestration and degradation of the GluA2 AMPA receptor subunit
Author(s) -
Beske Phillip H.,
Byrnes Nicole M.,
AstrucDiaz Fanny,
Jackson Darrell A.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13005
Subject(s) - ampa receptor , mediator , nadph oxidase , protein subunit , chemistry , identification (biology) , ischemia , receptor , neuroscience , microbiology and biotechnology , biophysics , glutamate receptor , biology , biochemistry , reactive oxygen species , medicine , ecology , gene
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 ( AMPAR s). This change in AMPAR subunit composition leads to an increase in surface expression of GluA2‐lacking Ca 2+ /Zn 2+ permeable AMPAR s. These GluA2‐lacking AMPAR s 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.A hallmark of post‐ischemic reperfusion (I/R) injury is a change in subunit composition of synaptic AMPARs. This change in AMPAR subunit composition leads to an increase in surface expression of Ca 2+ /Zn 2+ ‐permeable AMPARs. We propose a novel mechanistic concept in which increased NADPH oxidase activity during reperfusion is the trigger that underlies the change in subunit composition of synaptic AMPARs; changing from Ca 2+ /Zn 2+ ‐impermeable to Ca 2+ /Zn 2+ ‐permeable. We think that these findings should provide valuable strategy for treatment of ischemic/reperfusion brain injury. AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; GDI, guanyl nucleotide dissociation inhibitor; GDP, guanosine diphosphate; 3/6, MKK 3/6, MAPKK; GRIP, glutamate receptor interacting protein; GTP, guanosine‐5′‐triphosphate; NADPH, nicotinamide adenine dinucleotide phosphate; p38 MAPK, p38 mitogen‐activated protein kinases; PICK1, PRKCA‐binding protein; PKCα, protein kinase C alpha; PSD, post‐synaptic density.