N-Methyl-d-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease
Abstract
N-methyl-D-aspartate (NMDA) receptors are the major mediator of excitotoxicity. Although physiological activation of the NMDA receptor is necessary for cell survival, overactivation is a signal for cell death. Several pathways are activated through NMDA receptor stimulation, most of which can contribute to excitotoxicity. These include events leading to mitochondrial dysfunction, activation of calcium-dependent enzymes, and activation of mitogen-activated protein kinase pathways. Understanding the role of these mechanisms is important in developing agents that block excitotoxicity without inhibiting functions necessary for survival. NMDA receptor subtypes may be responsible for mediating separate pathways, and subtype-specific inhibition has shown promising results in some neurological models. This review examines the roles of NMDA receptor subtypes in excitotoxicity and neurological disorders.
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Fyn is mainly responsible for phosphorylation of the NR2 subunits of NMDAR, which is known to enhance their conductance.
“The SFK, Fyn, is mainly responsible for the phosphorylation of the NR2 subunits of the NMDAR, which is known to enhance their conductance (reviewed in Ref. 28) (Figs.2A and 3A).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [28]
Low activity of NMDA receptors produces symptoms of schizophrenia.
“Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [3]
Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke.
“Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [3]
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Solenski, N. J., Kostecki, V. K., Dovey, S. L., & Periasamy, A. (2003) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2003.08.011 · Cited by 32 · see citing works
Ekinci, F. J., & SHEA, T. B. (1999) · Brain Research · doi:10.1016/s0006-8993(99)02146-0 · Cited by 26 · see citing works
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Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., Dessain, S. K., Rosenfeld, M. R., Balice-Gordon, R., & Lynch, D. R. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70224-2 · Cited by 3,488 · see citing works
Self-citationDalmau, J., Tüzün, E., Wu, H., Masjuan, J., Rossi, J. E., Voloschin, A., Baehring, J. M., Shimazaki, H., Koide, R., King, D., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21050 · Cited by 2,492 · see citing works
Evolution of the Aging Brain Transcriptome and Synaptic Regulation
Loerch, P. M., Lu, T., Dakin, K. A., Vann, J. M., Isaacs, A., Geula, C., Wang, J., Pan, Y., Gabuzda, D. H., Li, C., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003329 · Cited by 334 · see citing works
Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B., & Tsai, L.-H. (2005) · Neuron · doi:10.1016/j.neuron.2005.10.033 · Cited by 277 · see citing works
Andrabi, S. A., Kang, H. C., Haince, J.-F., Lee, Y.-I., Zhang, J., Chi, Z., West, A. B., Koehler, R. C., Poirier, G. G., Dawson, T. M., et al. (2011) · Nature Medicine · doi:10.1038/nm.2387 · Cited by 216 · see citing works
The ketogenic diet and brain metabolism of amino acids: Relationship to the anticonvulsant effect
Yudkoff, M., Daikhin, Y., Melø, T. M., Nissim, I., Sonnewald, U., & Nissim, I. (2007) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.27.061406.093722 · Cited by 202 · see citing works
Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses
Wasser, C. R., & Herz, J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.766782 · Cited by 111 · see citing works
Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex
Henson, M. A., Roberts, A. C., Salimi, K., Vadlamudi, S., Hamer, R. M., Gilmore, J. H., Jarskog, L. F., & Philpot, B. D. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhn017 · Cited by 110 · see citing works
- Authors
- Waxman, E. A., & Lynch, D. R.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Lynch, David R.
- Venue
- The Neuroscientist
- Publisher
- SAGE Publications
- Published
- 2005-02
- Volume
- 11
- Issue
- 1
- Pages
- 37-49
- ISSN
- 1073-8584 (ISSN-L)
- 1089-4098
- OpenAlex
- W2121402661
- Cited by
- 372
- References
- 97
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 16 · 2020: 10 · 2019: 17 · 2018: 15 · 2017: 10 · 2016: 15 · 2015: 20 · 2014: 24 · 2013: 30 · 2012: 15
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Neuroscientist (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (T32MH014654, T32 MH 14654)
- National Institute of Neurological Disorders and Stroke (NS 45986)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- NMDA receptor, NMDA receptor subtypes, excitotoxicity, neurological disorders, mitochondrial dysfunction, calcium-dependent enzyme, MAPK signaling, neuronal cell death
- MeSH terms
- Animals, Central Nervous System, Humans, Synaptic Transmission, Neurotoxins, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Cell Death, Neurodegenerative Diseases, Protein Subunits
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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