title: Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5-Nrf2 pathway.
abstract: Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-d-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca²⁺ influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca²⁺ and protein kinase Cδ activation. Active protein kinase Cδ promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr(395), Ser(433) and Thr(439) that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.
authors.affiliation: Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain.|Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Jimenez-Blasco
authors.affiliation: Department of Physiology, Faculty of Veterinary, University of Extremadura, 10003 Caceres, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Santofimia-Castaño
authors.affiliation: Department of Physiology, Faculty of Veterinary, University of Extremadura, 10003 Caceres, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain.|Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Almeida
authors.affiliation: Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain.|Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors.forename: J P
authors.initials: JP
authors.lastname: Bolaños
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047468:Immunoprecipitation; D008055:Lipids / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008055:Lipids; C086724:Lipofectamine; D051267:NF-E2-Related Factor 2; D016194:Receptors, N-Methyl-D-Aspartate; D006861:Hydrogen Peroxide; D051360:Cyclin-Dependent Kinase 5