The C‐terminal domains of the NMDA receptor: How intrinsically disordered tails affect signalling, plasticity and disease
Abstract
NMDA receptors are part of the ionotropic glutamate receptor family, and are crucial for neurotransmission and memory. At the cellular level, the effects of activating these receptors include long‐term potentiation (LTP) or depression (LTD). The NMDA receptor is a stringently gated cation channel permeable to Ca 2+ , and it shares the molecular architecture of a tetrameric ligand‐gated ion channel with the other family members. Its subunits, however, have uniquely long cytoplasmic C‐terminal domains (CTDs). While the molecular gymnastics of the extracellular domains have been described in exquisite detail, much less is known about the structure and function of these CTDs. The CTDs vary dramatically in length and sequence between receptor subunits, but they all have a composition characteristic of intrinsically disordered proteins. The CTDs affect channel properties, trafficking and downstream signalling output from the receptor, and these functions are regulated by alternative splicing, protein–protein interactions, and post‐translational modifications such as phosphorylation and palmitoylation. Here, we review the roles of the CTDs in synaptic plasticity with a focus on biochemical mechanisms. In total, the CTDs play a multifaceted role as a modifier of channel function, a regulator of cellular location and abundance, and signalling scaffold control the downstream signalling output.
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Both ionotropic and metabotropic glutamate receptors have long cytoplasmic C-terminal intrinsically disordered domains (CTDs).
“Both have long cytoplasmic C-terminal intrinsically disordered domains (CTDs) [169, 255].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [169]
Many receptors require intrinsically disordered cytoplasmic tails to function properly.
“Many receptors require intrinsically disordered cytoplasmic tails to function properly [169, 281–283].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [169]
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Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels
Hansen, K. B., Wollmuth, L. P., Bowie, D., Furukawa, H., Menniti, F. S., Sobolevsky, A. I., Swanson, G. T., Swanger, S. A., Greger, I. H., Nakagawa, T., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000131 · Cited by 686 · see citing works
Intrinsically disordered proteins play diverse roles in cell signaling
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- Authors
- Warnet, X. L., Bakke Krog, H., Sevillano‐Quispe, O. G., Poulsen, H., & Kjaergaard, M.
- Affiliations
- Aarhus University (DK)
- Department of Molecular Biology and Genetics Aarhus University Aarhus Denmark
- Corresponding author
- Poulsen, Hanne
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2020-07-16
- Volume
- 54
- Issue
- 8
- Pages
- 6713-6739
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W3032632587
- Cited by
- 50
- References
- 240
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 11 · 2022: 10 · 2021: 9 · 2020: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Danmarks Grundforskningsfond (DNRF133)
- National Research Foundation (DNRF133)
- 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, C-terminal domain, intrinsically disordered proteins, synaptic plasticity, long-term potentiation, long-term depression, alternative splicing, protein phosphorylation, palmitoylation, protein-protein interaction, receptor trafficking, ionotropic glutamate receptors, memory
- MeSH terms
- Synaptic Transmission, Neuronal Plasticity, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation
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.
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