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Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation
Open accessAbstract
Serine racemase (SR) generates D-serine, a coagonist with glutamate at NMDA receptors. We show that SR is physiologically S-nitrosylated leading to marked inhibition of enzyme activity. Inhibition involves interactions with the cofactor ATP reflecting juxtaposition of the ATP-binding site and cysteine-113 (C113), the site for physiological S-nitrosylation. NMDA receptor physiologically enhances SR S-nitrosylation by activating neuronal nitric-oxide synthase (nNOS). These findings support a model whereby postsynaptic stimulation of nitric-oxide (NO) formation feeds back to presynaptic cells to S-nitrosylate SR and decrease D-serine availability to postsynaptic NMDA receptors.
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“Several proteins related to glutamatergic neurotransmission contain modulatory redox sites, including glutamine synthase (Mustafa et al., 2007), serine racemase (responsible for synthesis of glycine, a NMDAR co-agonist, (Pinteaux et al., 1996)), and NMDARs (Choi et al., 2001).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Mustafa et al., 2007
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Cites
A synaptic model of memory: long-term potentiation in the hippocampus
Bliss, T. V. P., & Collingridge, G. L. (1993) · Nature · doi:10.1038/361031a0 · Cited by 11,566
Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme.
Bredt, D. S., & Snyder, S. H. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.2.682 · Cited by 3,308
Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase
Bredt, D. S., Hwang, P. M., Glatt, C. E., Lowenstein, C. J., Reed, R. R., & Snyder, S. H. (1991) · Nature · doi:10.1038/351714a0 · Cited by 2,354
Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum.
Bredt, D. S., & Snyder, S. H. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.9030 · Cited by 1,849
Boehning, D. F., & Snyder, S. H. (2003) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.26.041002.131047 · Cited by 1,235
D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor.
Mothet, J., Parent, A., Wolosker, H., Brady, R., Linden, D. J., Ferris, C., Rogawski, M., & Snyder, S. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.97.9.4926 · Cited by 1,164
Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory
Panatier, A., Theodosis, D. T., Mothet, J.-P., Touquet, B., Pollegioni, L., Poulain, D. A., & Oliet, S. H. R. (2006) · Cell · doi:10.1016/j.cell.2006.02.051 · Cited by 934
Wolosker, H., Blackshaw, S., & Snyder, S. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.23.13409 · Cited by 811
(S)NO Signals: Translocation, Regulation, and a Consensus Motif
Stamler, J. S., Toone, E. J., Lipton, S. A., & Sucher, N. J. (1997) · Neuron · doi:10.1016/s0896-6273(00)80310-4 · Cited by 679
Arancio, O., Kiebler, M., Lee, C. J., Lev-Ram, V., Tsien, R. Y., Kandel, E. R., & Hawkins, R. D. (1996) · Cell · doi:10.1016/s0092-8674(00)81797-3 · Cited by 357
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Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., & Dugan, L. L. (2007) · Science · doi:10.1126/science.1148045 · Cited by 585
Mustafa, A. K., Gadalla, M. M., & Snyder, S. H. (2009) · Science Signaling · doi:10.1126/scisignal.268re2 · Cited by 503
S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons
Nott, A., Watson, P. M., Robinson, J. D., Crepaldi, L., & Riccio, A. (2008) · Nature · doi:10.1038/nature07238 · Cited by 434
Redox Signaling Mediated by Thioredoxin and Glutathione Systems in the Central Nervous System
Ren, X., Zou, L., Zhang, X., Branco, V., Wang, J., Carvalho, C. M. L., Holmgren, A., & Lu, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6925 · Cited by 379
Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases
Nakamura, T., Tu, S., Akhtar, M. W., Sunico, C. R., Okamoto, S., & Lipton, S. A. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.005 · Cited by 361
Metadata
- Authors
- Mustafa, A. K., Kumar, M., Selvakumar, B., Ho, G. P. H., Ehmsen, J. T., Barrow, R. K., Amzel, L. M., & Snyder, S. H.
- Affiliations
- *Solomon H. Snyder Department of Neuroscience and
- Departments of †Biophysics and Biophysical Chemistry,
- Johns Hopkins University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-02-20
- Volume
- 104
- Issue
- 8
- Pages
- 2950-2955
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1815287
- OpenAlex
- W2147808921
- Cited by
- 136
- References
- 21
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 1 · 2022: 6 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 8 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 12 · 2013: 12 · 2012: 13
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH018501, R37MH018501, MH-18501)
- National Institute on Drug Abuse (DA 00074, K05DA000074)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- serine racemase, S-nitrosylation, D-serine, NMDA receptor co-agonist, product inhibition, ATP binding site, neuronal nitric oxide synthase, nitric oxide, presynaptic modulation
- MeSH terms
- Serine Racemase, Adenosine Triphosphate, Amino Acid Sequence, Animals, Coenzymes, Cysteine, Enzyme Activation, Humans, Models, Molecular, Models, Neurological, Molecular Sequence Data, Nitric Oxide, Serine, Receptors, N-Methyl-D-Aspartate, Racemases and Epimerases, Feedback, Physiological, S-Nitrosoglutathione, Mice, Nitric Oxide Synthase Type I
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