Three Pairs of Cysteine Residues Mediate Both Redox and Zn2+Modulation of the NMDA Receptor
Open accessAbstract
NMDA receptor activity is modulated by various compounds, including sulfhydryl redox agents and Zn(2+). In addition to a slow and persistent component of redox modulation common to all NMDA receptors, NR1/NR2A receptors uniquely have a rapid and reversible component that has been variously attributed to redox or Zn(2+) effects. Here we show that this rapid modulatory effect can be described by two time constants with relatively fast ( approximately 6 sec) and intermediate (60 sec) half lives, and it is likely to be attributable to both redox agents and Zn(2+). Using site-directed mutagenesis, we identified three pairs of cysteine residues that underlie the various kinetic components of redox modulation of NMDA-evoked currents in Xenopus oocytes expressing NR1/NR2A receptors: (1) Cys 87 and Cys 320 in NR2A underlie the fast component, (2) Cys 79 and Cys 308 in NR1 underlie the intermediate component, and (3) Cys 744 and Cys 798 in NR1 underlie the persistent component. Mutation of these redox-sensitive cysteine residues also affects high-affinity, voltage-independent Zn(2+) inhibition that is specific to NR1/NR2A receptors. Exposure to methanethiosulfonate agents that modify cysteine residues did not block the Zn(2+) inhibition. Thus, these cysteine residues do not appear to coordinate Zn(2+) directly. Instead, the redox status of these cysteine residues may modulate the sensitivity of the receptor to Zn(2+).
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Several proteins related to glutamatergic neurotransmission contain modulatory redox sites, including glutamine synthase, serine racemase, and NMDARs.
“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 Choi et al., 2001
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- Authors
- Choi, Y.-B., Chen, H.-S. V., & Lipton, S. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-01-15
- Volume
- 21
- Issue
- 2
- Pages
- 392-400
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6763802
- OpenAlex
- W2129034780
- Cited by
- 132
- References
- 52
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 9 · 2013: 2 · 2012: 9
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- Allergan
- National Institute of Mental Health (MH12255, F30MH012255)
- National Eye Institute (R01 EY 05477, R01EY005477)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD29587, P01HD029587)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- NMDA receptor, redox modulation, zinc modulation, cysteine residues, zinc inhibition, site-directed mutagenesis, ion channel modulation
- MeSH terms
- Animals, Binding Sites, Cells, Cultured, Cysteine, Dithiothreitol, Dose-Response Relationship, Drug, Drug Synergism, Glycine, Histidine, Mesylates, Oocytes, Oxidation-Reduction, Structure-Activity Relationship, Sulfhydryl Reagents, Transfection, Xenopus, Zinc, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Mutagenesis, Site-Directed, Patch-Clamp Techniques
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