N-Methyl-D-aspartate Receptors: Subunit Assembly and Trafficking to the Synapse
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NMDA 1The abbreviations used are: NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ER, endoplasmic reticulum; AMPAR, AMPA receptor; MAGUK, membrane-associated guanylate kinase; PSD, postsynaptic density; PKC, protein kinase C. receptors (NMDARs) are members of the glutamate receptor family of ion channels, which also includes the AMPA, kainate, and delta subtypes of receptors. NMDARs are present at excitatory synapses in the mammalian central nervous system and have specialized characteristics, including voltage-dependent block by magnesium, calcium permeability, and slow deactivation kinetics (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). Biophysical studies of NMDARs outline a complex pharmacology with multiple modulatory sites (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). Calcium entry through the NMDAR regulates numerous downstream signaling pathways leading to both short term and long term neuronal changes (recently reviewed in Ref. 2Hardingham G.E. Bading H. Trends Neurosci. 2003; 26: 81-89Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). This calcium flux is also necessary for inducing long term potentiation, a molecular model of memory (3Nicoll R.A. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 721-726Crossref PubMed Scopus (160) Google Scholar), suggesting that NMDARs are key players in memory formation and synaptic plasticity. In addition, NMDAR dysfunction is implicated in numerous neurologic and psychiatric disorders, and therapeutic agents that target NMDARs have been studied. The present review will focus on the subunit assembly and trafficking of NMDA receptors, areas of significant progress in recent years. The NMDAR family is made up of NR1, NR2, and NR3 subunits. Functional NMDARs are heteromeric complexes containing both NR1 and NR2 subunits (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). NR3 subunits can assemble with NR1-NR2 complexes to depress NMDAR responses and can also assemble with NR1 alone to form a glycine receptor, with the role of this receptor in the central nervous system still unclear (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). The structure of the NMDAR is outlined in Fig. 1. There is a single NR1 subunit that can exist in eight different variants generated by alternative splicing at three sites within the protein, one in the N terminus and two in the C terminus (4Carroll R.C. Zukin R.S. Trends Neurosci. 2002; 25: 571-577Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). The N-terminal cassette (the N1 cassette or exon 5) is extracellular and affects regulation of the channel with modulators like protons and spermine (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar), whereas the C-terminal cassettes are mediators of protein interactions (4Carroll R.C. Zukin R.S. Trends Neurosci. 2002; 25: 571-577Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Splicing in the C terminus regulates expression of three different cassettes, the C1, C2, and C2′ cassettes (as shown in Fig. 1). NR1 subunits can be formed either containing or lacking the C1 cassette. If the C2 cassette is absent, the first stop codon is lost and the separate C2′ cassette is expressed in the subunit instead. Therefore, all NR1 contains either the C2 or C2′ cassette. The C1 cassette contains an endoplasmic reticulum (ER) retention signal, which can be overcome by expression of the C2′ cassette, suggesting that splicing of the C-terminal tail of NR1 may regulate receptor trafficking (as reviewed in Refs. 4Carroll R.C. Zukin R.S. Trends Neurosci. 2002; 25: 571-577Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar and 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Alternatively spliced forms of NR1 have different regional and developmental expression profiles (6Zukin R.S. Bennett M.V.L. Trends Neurosci. 1995; 18: 306-313Abstract Full Text PDF PubMed Scopus (403) Google Scholar) and are regulated by neuronal activity (7Mu Y. Otsuka T. Horton A.C. Scott D.B. Ehlers M.D. Neuron. 2003; 40: 581-594Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar), generating a large degree of channel diversity. NR2 subunits contain the glutamate-binding site, and four genes encoding NR2 subunits (NR2A–D) have been cloned. The sp
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Self-citation
- Authors
- Prybylowski, K., & Wenthold, R. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Prybylowski, Kate
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 279
- Issue
- 11
- Pages
- 9673-9676
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2054661844
- Cited by
- 137
- References
- 61
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 7
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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, receptor trafficking, synaptic localization, glutamate receptors, AMPA receptors, MAGUK proteins, postsynaptic density, endoplasmic reticulum, protein kinase C, long-term potentiation, synaptic plasticity, memory formation, NMDA receptor antagonists
- MeSH terms
- Animals, Binding Sites, Cell Membrane, Endoplasmic Reticulum, Humans, Models, Biological, Phosphorylation, Protein Binding, Synapses, Receptors, N-Methyl-D-Aspartate, Alternative Splicing, Protein Structure, Tertiary, Protein Transport
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