NMDA receptor activation dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840
Open accessAbstract
Phosphorylation-dependent changes in AMPA receptor function have a crucial role in activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Although three previously identified phosphorylation sites in AMPA receptor glutamate receptor 1 (GluR1) subunits (S818, S831, and S845) appear to have important roles in LTP and LTD, little is known about the role of other putative phosphorylation sites in GluR1. Here, we describe the characterization of a recently identified phosphorylation site in GluR1 at threonine 840. The results of in vivo and in vitro phosphorylation assays suggest that T840 is not a substrate for protein kinases known to phosphorylate GluR1 at previously identified phosphorylation sites, such as protein kinase A, protein kinase C, and calcium/calmodulin-dependent kinase II. Instead, in vitro phosphorylation assays suggest that T840 is a substrate for p70S6 kinase. Although LTP-inducing patterns of synaptic stimulation had no effect on GluR1 phosphorylation at T840 in the hippocampal CA1 region, bath application of NMDA induced a strong, protein phosphatase 1- and/or 2A-mediated decrease in T840 phosphorylation. Moreover, GluR1 phosphorylation at T840 was transiently decreased by a chemical LTD induction protocol that induced a short-term depression of synaptic strength and persistently decreased by a chemical LTD induction protocol that induced a lasting depression of synaptic transmission. Together, our results show that GluR1 phosphorylation at T840 is regulated by NMDA receptor activation and suggest that decreases in GluR1 phosphorylation at T840 may have a role in LTD.
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During LTD, GluA1 T840 is dephosphorylated by PP1/PP2A and S845 by CaN.
“GluA1 undergoes dephosphorylation of T840 and S845 during LTD by protein phosphatases PP1/PP2A and CaN, respectively (Delgado et al., 2007, Toda and Huganir, 2015, Lee et al., 1998, Sanderson et al., 2016).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Delgado et al., 2007
The Results sections on chem-LTD and T840 phosphatases report persistent T840 dephosphorylation during chemical LTD and show that inhibiting PP1/PP2A prevents NMDA-induced T840 dephosphorylation. They do not establish the same change during synaptically induced LTD, and the paper does not identify CaN as the phosphatase responsible for S845 dephosphorylation. (LLM, conf=0.87)
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Coward, L. A. (2013) · Springer eBooks · doi:10.1007/978-94-007-7107-9_5
Interactions between Hebbian and Homeostatic Synaptic Plasticity in Hippocampal Circuits.
Iliff, A. J. (2014) · Deep Blue (University of Michigan)
Novel Roles of the GPI-Anchor Cleaving Enzyme, GDE2, in Hippocampal Synaptic Morphology and Function
Daudelin, D., Sama-Borbon, D., Zhang, N., & Sockanathan, S. (2025) · eNeuro · doi:10.1523/eneuro.0102-25.2025
Phosphoprofile reorganization of the actin binding protein Drebrin during long term depression
Silva, R. P., Mack, T. G. A., Kirchner, M., Mertins, P., Eickholt, B. J., & Kreis, P. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1697642
Règle de STDP en calcium physiologique
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Transport intracellulaire des récepteurs AMPA et régulation par leurs protéines associées
Bonnet, C. (2021) · theses.fr (ABES) · doi:10.70675/a51a45f6zee8cz4c6az85a5z8b01dfd87159
Kurup, P., Thielbar, A. R., Jasinski, E., Galvan, B., Singh, T., Kanuru, S., Gor, H. T., Rommel, A. V., Parungao, M. R., Parada, D. B. P., et al. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1777680
Self-citationA study of the molecular basis of the interaction between AMPARs and their auxiliary subunits
Krol, K. (2015) · UCL Discovery (University College London)
- Authors
- Delgado, J. Y., Coba, M., Anderson, C. N. G., Thompson, K. R., Gray, E. E., Heusner, C. L., Martin, K. C., Grant, S. G. N., & O'Dell, T. J.
- Affiliations
- University of California, Los Angeles (US)
- Wellcome Sanger Institute (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-11-28
- Volume
- 27
- Issue
- 48
- Pages
- 13210-13221
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2851143
- OpenAlex
- W2036834190
- Cited by
- 62
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 6 · 2013: 8 · 2012: 1
- FWCI
- 1.73
- 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
- National Science Foundation
- W. M. Keck Foundation
- National Alliance for Research on Schizophrenia and Depression
- Wellcome Trust (077155)
- National Institute of Mental Health (R01MH060919)
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- AMPA receptors, GluR1, phosphorylation, NMDA receptor activation, dephosphorylation, protein phosphatase 1, protein phosphatase 2A, p70 S6 kinase, long-term depression, long-term potentiation, synaptic plasticity, hippocampal CA1
- MeSH terms
- Adrenergic beta-Agonists, Analysis of Variance, Animals, Cells, Cultured, Enzyme Inhibitors, Colforsin, Hippocampus, Humans, Isoproterenol, Mice, Inbred C57BL, Neurons, Threonine, Transfection, Receptors, N-Methyl-D-Aspartate, Mutagenesis, Long-Term Potentiation, Receptors, AMPA, Excitatory Amino Acid Agents, Excitatory Postsynaptic Potentials, Protein Array Analysis, Mice, In Vitro Techniques
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