ArticleCell death and differentiation2015
Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5-Nrf2 pathway.
Article in Cell death and differentiation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 186 citations in OpenAlex.
- The neuroimmune-glutamate hypothesis of addiction.Neuroscience and biobehavioral reviews · 2026Review
- Low Dose Ketamine Preconditions Astrocyte Mitochondria to Achieve Antidepressant Efficacy via Adenosine, Humanin, and Melatonin Upregulation and Efflux.Alpha psychiatry · 2026Article
- Metabolic crosstalk in the ageing brain: astrocyte-neuron coupling as a target for homeostatic restoration and therapy.Translational neurodegeneration · 2026Review
- Astrocytic Redox Homeostasis as a Metabolic Modulator of DNA Damage and Repair in the Ischemic Penumbra.Cells · 2026Review
- Artesunate overcomes oxaliplatin resistance in colorectal cancer by inducing ferroptosis through inhibition of the CDK5/Nrf2/GPX4 pathway.Apoptosis : an international journal on programmed cell death · 2026Article
- Targeting Glutamate Excitotoxicity With Memantine Modulates Glial Response and Protects Motoneurons After Spinal Root Lesion.Journal of neurochemistry · 2026Article
- Multi-modal label-free imaging of cellular metabolism and oxidative stress in 3D brain tissue models.Communications biology · 2025Article
- The neuron-astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease.Nature metabolism · 2025Review
- Neuron-Glia Crosstalk in the Regulation of Astrocytic Antioxidative Mechanisms Following CNS Injury.Antioxidants (Basel, Switzerland) · 2025Review
- Calcium Signaling in Astrocytes and Its Role in the Central Nervous System Injury.Molecular neurobiology · 2025Review
- Methylglyoxal, a Knot to Be Untied in Brain Glucose Hypometabolism.Metabolites · 2025Review
- Neural Metabolic Networks: Key Elements of Healthy Brain Function.Journal of neurochemistry · 2025Review
- Astrocyte-to-neuron HNature metabolism · 2025Article
- Inflammasomes in Alzheimer's Progression: Nrf2 as a Preventive Target.Antioxidants (Basel, Switzerland) · 2025Review
- Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.Biomolecules · 2025Review
- GLSP mitigates vascular aging by promoting Sirt7-mediated Keap1 deacetylation and Keap1-Nrf2 dissociation.Theranostics · 2025Article
- (Re)building the nervous system: A review of neuron-glia interactions from development to disease.Journal of neurochemistry · 2025Review
- System Xc-pathway as a potential regulatory target in neurological disorders.Frontiers in pharmacology · 2025Review
- The molecular determinants regulating redox signaling in diabetic endothelial cells.Frontiers in pharmacology · 2025Review
- Multitarget Effects of Nrf2 Signalling in the Brain: Common and Specific Functions in Different Cell Types.Antioxidants (Basel, Switzerland) · 2024Review
44 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.