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Cited by 42Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersAmino Acid Enzymes and Metabolism

The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences

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McKay, Sean, Ryan, Tomás J., McQueen, Jamie, Indersmitten, Tim, Marwick, Katie F.M., Hasel, Philip, Kopanitsa, Maksym V., Baxter, Paul S. +7 more·2018·Cell Reports
DOI 10.1016/j.celrep.2018.09.089PMC PMC6218242
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Abstract

The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. This "switch" is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse. However, these models remain untested in the context of endogenous NMDARs. We show that, although mutating the endogenous GluN2B CaMKII site has secondary effects on GluN2B CTD phosphorylation, the developmental changes in NMDAR composition occur normally and measures of plasticity and synaptogenesis are unaffected. Moreover, the switch proceeds normally in mice that have the GluN2A CTD replaced by that of GluN2B and commences without an observable decline in GluN2B levels but is impaired by GluN2A haploinsufficiency. Thus, GluN2A expression levels, and not GluN2 subtype-specific CTD-driven events, are the overriding factor in the developmental switch in NMDAR composition.

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  • Mutations in the GluN2B CTD that cannot bind CaMKII, or competing constructs, produce highly variable effects on LTP, ranging from complete block to no block.

    “The second approach utilizes mutations in the CTD of GluN2B that cannot bind CaMKII as replacement for the wt (CaMKII L1298A/R1300Q) (120, 121, 230) or either competing with overexpressed full-length constructs (GluN2B R1300S/Q1303D) (231) or competing by expressing just the wt GluN2B CTD (839–1482) (232). The results are highly variable as reviewed in Ref. 233, ranging from complete block of LTP”

    From Synaptic memory and CaMKII (2023) · cites this paper as [230]

    The Results report that the paper’s GluN2B CaMKII-binding-site mutant showed no significant difference in theta-burst LTP from wild type. But its knockin is L1298A/R1300N/S1303D, not the L1298A/R1300Q variant named alongside this citation. The broader range from complete block to no block is attributed in the citing sentence to a separate review, not to this paper. (LLM, conf=0.87)

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Authors
McKay, S., Ryan, T. J., McQueen, J., Indersmitten, T., Marwick, K. F. M., Hasel, P., Kopanitsa, M. V., Baxter, P. S., Martel, M.-A., Kind, P. C., Wyllie, D. J. A., O’Dell, T. J., Grant, S. G. N., Hardingham, G. E., & Komiyama, N. H.
Affiliations
  • UK Dementia Research Institute (GB)
  • The University of Melbourne (AU)
  • University of California, Los Angeles (US)
  • Simons Initiative for the Developing Brain (GB)
  • Hammersmith Hospital (GB)
  • University of Edinburgh (GB)
  • Wellcome Sanger Institute (GB)
Corresponding author
  • Hardingham, Giles E.
  • Komiyama, Noboru H.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-10
Volume
25
Issue
4
Pages
841-851.e4
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2018.09.089
PMC
PMC6218242
OpenAlex
W2896317215
Cited by
42
References
4
Citations by year
2026: 3 · 2025: 4 · 2024: 8 · 2023: 6 · 2022: 3 · 2021: 11 · 2020: 3 · 2019: 4
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • MRC
  • Wellcome Trust
  • Alzheimer’s Research UK
  • Alzheimer's Society
  • Wellcome (202932)
  • European Research Council (695568)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
NMDA receptor, GluN2A, GluN2B, C-terminal domain phosphorylation, synaptogenesis, forebrain development
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Mice, Inbred C57BL, Mutation, Phosphorylation, Synapses, Theta Rhythm, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Protein Subunits, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Neurogenesis

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