Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway
Open accessAbstract
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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NFE2L2-dependent gene expression is activated by mild oxidative stress.
“However, this deprives neurons of a useful adaptive response, since NFE2L2-dependent gene expression is activated by mild oxidative stress 82,84,85 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [85]
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PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
Grynkiewicz, G., Poenie, M., & Tsien, R. Y. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)83641-4 · Cited by 21,722 · see citing works
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023 · see citing works
Tietze, F. (1969) · Analytical Biochemistry · doi:10.1016/0003-2697(69)90064-5 · Cited by 6,077 · see citing works
Pellerin, L., & Magistretti, P. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.22.10625 · Cited by 2,927 · see citing works
Rothstein, J. D., Dykes-Hoberg, M., Pardo, C. A., Bristol, L. A., Jin, L., Kuncl, R. W., Kanai, Y., Hediger, M. A., Wang, Y., Schielke, J. P., et al. (1996) · Neuron · doi:10.1016/s0896-6273(00)80086-0 · Cited by 2,534 · see citing works
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644 · cited 1× · see citing works
“tive oxygen species (ROS) responsible for oxidative damage and neurodegeneration.(1,2) To defend themselves against”
BackgroundGliotransmitters Travel in Time and Space
Araque, A., Carmignoto, G., Haydon, P. G., Oliet, S. H. R., Robitaille, R., & Volterra, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.007 · Cited by 1,308 · see citing works
The emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,304 · see citing works
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Hayes, J. D., & McMahon, M. J. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.12.008 · Cited by 870 · see citing works
Herrero-Mendez, A., Almeida, A., Fernández, E., Maestre, C., Moncada, S., & Bolaños, J. P. (2009) · Nature Cell Biology · doi:10.1038/ncb1881 · Cited by 844 · see citing works
Self-citationActivity-dependent regulation of energy metabolism by astrocytes: an update
Pellerin, L., Bouzier‐Sore, A., Aubert, A., Serres, S., Merle, M., Costalat, R., & Magistretti, P. J. (2007) · Glia · doi:10.1002/glia.20528 · Cited by 805 · see citing works
Evidence Supporting the Existence of an Activity-Dependent Astrocyte-Neuron Lactate Shuttle
Pellerin, L., Pellegri, G., Bittar, P. G., Charnay, Y., Bouras, C., Martin, J., Stella, N., & Magistretti, P. J. (1998) · Developmental Neuroscience · doi:10.1159/000017324 · Cited by 757 · see citing works
Molecular pathways to neurodegeneration
Bossy-Wetzel, E., Schwarzenbacher, R., & Lipton, S. A. (2004) · Nature Medicine · doi:10.1038/nm1067 · Cited by 740 · see citing works
Astrocyte–neuron metabolic relationships: for better and for worse
Allaman, I., Bélanger, M., & Magistretti, P. J. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2010.12.001 · Cited by 639 · see citing works
Dringen, R., Pfeiffer, B., & Hamprecht, B. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-02-00562.1999 · Cited by 589 · see citing works
Bloom, D. A., & Jaiswal, A. K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307633200 · Cited by 523 · see citing works
Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons
Yang, J., Ruchti, E., Petit, J.-M., Jourdain, P., Grenningloh, G., Allaman, I., & Magistretti, P. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322912111 · Cited by 504 · see citing works
Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Papadia, S., Soriano, F. X., Léveillé, F., Martel, M.-A., Dakin, K. A., Hansen, H. H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., et al. (2008) · Nature Neuroscience · doi:10.1038/nn2071 · Cited by 498 · see citing works
Almeida, Á., Moncada, S., & Bolaños, J. P. (2003) · Nature Cell Biology · doi:10.1038/ncb1080 · Cited by 481 · see citing works
Self-citationVaughn, A. E., & Deshmukh, M. (2008) · Nature Cell Biology · doi:10.1038/ncb1807 · Cited by 408 · see citing works
Calpain-dependent Proteolytic Cleavage of the p35 Cyclin-dependent Kinase 5 Activator to p25
Kusakawa, G.-I., Saito, T., Onuki, R., Ishiguro, K., Kishimoto, T., & Hisanaga, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m907757199 · Cited by 381 · see citing works
Lactate is a Preferential Oxidative Energy Substrate over Glucose for Neurons in Culture
Bouzier-Sore, A.-K., Voisin, P., Canioni, P., Magistretti, P. J., & Pellerin, L. (2003) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000091761.61714.25 · Cited by 328 · see citing works
Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors
Wang, J., Liu, S., Fu, Y., Wang, J. H.-C., & Lu, Y. (2003) · Nature Neuroscience · doi:10.1038/nn1119 · Cited by 270 · see citing works
Verkhratsky, A., & Kirchhoff, F. (2007) · The Neuroscientist · doi:10.1177/1073858406294270 · Cited by 265 · see citing works
Antioxidant and bioenergetic coupling between neurons and astrocytes
Fernandez-Fernandez, S., Almeida, A., & Bolaños, J. P. (2012) · Biochemical Journal · doi:10.1042/bj20111943 · Cited by 247 · see citing works
Self-citationASC is a Bax adaptor and regulates the p53–Bax mitochondrial apoptosis pathway
Ohtsuka, T., Ryu, H., Minamishima, Y. A., Macip, S., Sagara, J., Nakayama, K. I., Aaronson, S. A., & Lee, S. W. (2004) · Nature Cell Biology · doi:10.1038/ncb1087 · Cited by 243 · see citing works
Astrocytes of the mouse neocortex express functional N‐methyl‐D‐aspartate receptors
Schipke, C. G., Ohlemeyer, C., Matyash, M., Nolte, C., Kettenmann, H., & Kirchhoff, F. (2001) · The FASEB Journal · doi:10.1096/fj.00-0439fje · Cited by 202 · see citing works
Characterisation of the Expression of NMDA Receptors in Human Astrocytes
Lee, M.-C., Ting, K.-K., Adams, S., Brew, B., Chung, R., & Guillemin, G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014123 · Cited by 182 · see citing works
Zhou, C., Wee, S., Rhee, E., Naumann, M., Dubiel, W., & Wolf, D. A. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00136-9 · Cited by 180 · see citing works
Phospholipase activation triggers apoptosis in photosensitized mouse lymphoma cells.
Agarwal, M. L., Larkin, H. E., Zaidi, S. I. A., Mukhtar, H., & Oleinick, N. L. (1993) · PubMed · Cited by 177 · see citing works
Protein Kinase Cδ (PKCδ): Activation Mechanisms and Functions
Kikkawa, U., Matsuzaki, H., & Yamamoto, T. (2002) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a003294 · Cited by 168 · see citing works
Almeida, Á., & Bolaños, J. P. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00276.x · Cited by 157 · see citing works
Self-citationHaskew-Layton, R. E., Payappilly, J. B., Smirnova, N. A., Ma, T. C., Chan, K. K., Murphy, T. H., Guo, H., Langley, B. C., Rukhsana Sultana, A., Butterfield, D. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003996107 · Cited by 151 · see citing works
Properties of K + and Cl − channels and their involvement in proliferation of rat microglial cells
Schlichter, L. C., Sakellaropoulos, G., Ballyk, B. A., Pennefather, P., & Phipps, D. J. (1996) · Glia · doi:10.1002/(sici)1098-1136(199607)17:3 · Cited by 150 · see citing works
Rodriguez‐Rodriguez, P., Fernandez, E., Almeida, Á., & Bolaños, J. P. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.33 · Cited by 147 · see citing works
Self-citationSynaptic NMDA Receptors Mediate Hypoxic Excitotoxic Death
Wroge, C. M., Hogins, J., Eisenman, L., & Mennerick, S. J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6371-11.2012 · Cited by 142 · see citing works
Bell, K. F., Al-Mubarak, B., Fowler, J. H., Baxter, P. S., Gupta, K., Tsujita, T., Chowdhry, S., Patani, R., Chandran, S., Horsburgh, K., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015229108 · Cited by 133 · see citing works
Dringen, R., Kranich, O., & Hamprecht, B. (1997) · Neurochemical Research · doi:10.1023/a:1027310328310 · Cited by 129 · see citing works
Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity
Maestre, C., Delgado‐Esteban, M., Sánchez, J. C. G., Bolaños, J. P., & Almeida, Á. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.195 · Cited by 126 · see citing works
Self-citationCDK5 is essential for TGF-β1-induced epithelial-mesenchymal transition and breast cancer progression
Liang, Q. Y., Li, L., Zhang, J., Yang, L., Wang, L., Liu, D., Feng, J., Hou, P., Yao, R., Zhang, Y., et al. (2013) · Scientific Reports · doi:10.1038/srep02932 · Cited by 123 · see citing works
Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes
Palygin, O., Lalo, U., & Pankratov, Y. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01374.x · Cited by 121 · see citing works
Regulation and role of cyclin‐dependent kinase activity in neuronal survival and death
Hisanaga, S., & Endo, R. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07050.x · Cited by 117 · see citing works
(2011) · Proceedings of the National Academy of Sciences · doi:10.1073/iti0111108 · Cited by 104 · see citing works
Ionotropic glutamate receptors in astrocytes
Seifert, G., & Steinhäuser, C. (2001) · Progress in brain research · doi:10.1016/s0079-6123(01)32083-6 · Cited by 102 · see citing works
CAND1-Mediated Substrate Adaptor Recycling Is Required for Efficient Repression of Nrf2 by Keap1
Lo, S., & Hannink, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.4.1235-1244.2006 · Cited by 99 · see citing works
Neuronal activity regulates astrocytic Nrf2 signaling
Habas, A., Hahn, J., Wang, X., & Margeta, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208764110 · Cited by 97 · see citing works
Cdk5 Modulation of Mitogen-activated Protein Kinase Signaling Regulates Neuronal Survival
Zheng, Y.-L., Li, B., Kanungo, J., Kesavapany, S., Amin, N. D., Grant, P. G., & Pant, H. C. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-09-0851 · Cited by 75 · see citing works
Susarla, B. T. S., & Robinson, M. B. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01886.x · Cited by 62 · see citing works
PKCδ regulates cortical radial migration by stabilizing the Cdk5 activator p35
Zhao, C.-T., Li, K., Li, J.-T., Zheng, W., Liang, X.-J., Geng, A.-Q., Li, N., & Yuan, X.-B. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0812872106 · Cited by 62 · see citing works
Purification of Rat and Mouse Astrocytes by ImmunopanningPreprint
Foo, L. C. (2013) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot074211 · Cited by 62 · see citing works
Dos-Anjos, S., Martínez‐Villayandre, B., Montori, S., Regueiro-Purriños, M. M., Gonzalo-Orden, J. M., & Fernández‐López, A. (2008) · Neurochemistry International · doi:10.1016/j.neuint.2008.09.016 · Cited by 35 · see citing works
Nrf2 target genes can be controlled by neuronal activity in the absence of Nrf2 and astrocytes
Deighton, R. F., Márkus, N. M., Al-Mubarak, B., Bell, K. F. S., Papadia, S., Meakin, P. J., Chowdhry, S., Hayes, J. D., & Hardingham, G. E. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402097111 · Cited by 30 · see citing works
Young, K. W., Garro, M. A., Challiss, R. A. J., et al. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02458.x · Cited by 22 · see citing works
Salazar, M., Pariente, J. A., Salido, G. M., et al. (2008) · Toxicology · doi:10.1016/j.tox.2007.12.002 · Cited by 22 · see citing works
Habas, A., Hahn, J., Wang, X., & Margeta, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403291111 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. Molecular pathways to neurodegenera- tion. Nat Med 2004; 10: S2-S9.
- Conti F, DeBiasi S, Minelli A, Melone M. Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes. Glia 1996; 17: 254-258.
Cited by
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Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
Hardingham, G. E., & Do, K. Q. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.19 · Cited by 304 · see citing works
Bioenergetics and redox adaptations of astrocytes to neuronal activity
Bolaños, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13486 · Cited by 262 · see citing works
Self-citationMolecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · see citing works
“Other recent experimental evidence linking AD to the Nrf2 pathway showed that methysticin, a kavalactone activating the Nrf2 signaling pathway, reduced neuroinflammation, loss of memory and damage as a result of oxidative stress in the hippocampus of APP/Psen1 mice [161].”
BackgroundInfluentialHaddad, M., Hervé, V., Ben Khedher, M. R., Rabanel, J.-M., & Ramassamy, C. (2021) · Antioxidants & Redox Signaling · doi:10.1089/ars.2020.8129 · Cited by 68 · see citing works
- Authors
- Jimenez-Blasco, D., Santofimia-Castaño, P., Gonzalez, A., Almeida, A., & Bolaños, J. P.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Bolaños, J P
- ORCID
- Bolaños, J P
- Venue
- Cell Death & Differentiation
- Published
- 2015-04-24
- Volume
- 22
- Issue
- 11
- Pages
- 1877-1889
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4648333
- OpenAlex
- W2111623179
- Cited by
- 196
- References
- 57
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 18 · 2023: 22 · 2022: 18 · 2021: 26 · 2020: 18 · 2019: 17 · 2018: 17 · 2017: 15 · 2016: 9 · 2015: 5
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- European Commission (608381)
- Junta de Extremadura (GR10010)
- National Institutes of Health (5r21da037678-02)
- Instituto de Salud Carlos III (RD12/0014, RD12/0043/0021, RD12/0014/0007, RD12/0043)
- European Regional Development Fund (GR10010, RD12/0014)
- National Institute on Drug Abuse (1R21DA037678-01, R21 DA037678)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- astrocytes, NMDA receptor, Nrf2, cyclin-dependent kinase 5, p35, oxidative stress, antioxidant defense, glutathione metabolism, intercellular communication, neuronal survival, phospholipase C, endoplasmic reticulum calcium release, protein kinase C delta, Nrf2 phosphorylation, mitochondrial reactive oxygen species, neurotransmission
- MeSH terms
- Animals, Astrocytes, Cell Survival, Cells, Cultured, Flow Cytometry, Humans, Hydrogen Peroxide, Lipids, Neurons, Blotting, Western, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, Immunoprecipitation, NF-E2-Related Factor 2, Cyclin-Dependent Kinase 5, Rats, Membrane Potential, Mitochondrial, HEK293 Cells
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