Journal
CELL DEATH AND DIFFERENTIATION
Volume 22, Issue 11, Pages 1877-1889Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2015.49
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Funding
- Junta de Extremadura-FEDER [GR10010]
- FIS Fellowship
- Gobierno de Extremadura (Consejeria de Empleo, Empresa e Innovacion) [PD10058]
- European Social Fund
- Spanish Ministerio de Economia y Competitividad [SAF2013-41177-R]
- Instituto de Salud Carlos III [RD12/0043/0021, PI12/00685, RD12/0014/0007]
- Junta de Castilla y Leon [SA003U13]
- SP3-People-MC-ITN program of the European Commission [608381 TINTIN]
- National Institutes of Drug Abuse/National Institutes of Health (NIH/NIDA) [1R21DA037678-01]
- European Regional Development Fund
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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 Cd activation. Active protein kinase Cd promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr395, Ser433 and Thr439 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.
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