Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins
Open accessAbstract
PSD-95, DLG, ZO-1 (PDZ) domain-mediated protein interactions have been shown to play important roles in the regulation of glutamate receptor function at excitatory synapses. Recent studies demonstrating the rapid regulation of AMPA receptor function during synaptic plasticity have suggested that AMPA receptor interaction with PDZ domain-containing proteins may be dynamically modulated. Here we show that PKC phosphorylation of the AMPA receptor GluR2 subunit differentially modulates its interaction with the PDZ domain-containing proteins GRIP1 and PICK1. The serine residue [serine-880 (Ser880)] in the GluR2 C-terminal sequence (IESVKI) critical for PDZ domain binding is a substrate of PKC and is phosphorylated in vivo. In vitro binding and coimmunoprecipitation studies show that phosphorylation of serine-880 within the GluR2 PDZ ligand significantly decreases GluR2 binding to GRIP1 but not to PICK1. Immunostaining of cultured hippocampal neurons demonstrates that the Ser880-phosphorylated GluR2 subunits are enriched and colocalized with PICK1 in the dendrites, with very little staining observed at excitatory synapses. Interestingly, PKC activation in neurons increases the Ser880 phosphorylation of GluR2 subunits and recruits PICK1 to excitatory synapses. Moreover, PKC stimulation in neurons results in rapid internalization of surface GluR2 subunits. These results suggest that GluR2 phosphorylation of serine-880 may be important in the regulation of the AMPA receptor internalization during synaptic plasticity.
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Phosphorylation of GluA2 S880 is required for cerebellar LTD; GluA2 K882A knock-in eliminates cerebellar LTD.
“Specifically, phosphorylation of GluA2 S880 is required as knock-in mutations that prevent phosphorylation of this site in mice (GluA2 K882A) eliminates cerebellar LTD (Chung et al., 2000, Steinberg et al., 2006).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Chung et al., 2000
The ‘PKC phosphorylates serine-880 of GluR2’ section establishes phosphorylation at this site, and the Discussion suggests it may regulate AMPA-receptor internalization during synaptic plasticity. The paper does not establish that S880 phosphorylation is required for cerebellar LTD or report that a K882A knock-in eliminates it. (LLM, conf=0.89)
Experimental — accuracy not yet measuredPhosphorylation of GluA2 S880 prevents GRIP1/2 binding, promotes interaction of the GluA2 PDZ ligand with PICK1, destabilizes GluA2 within the PSD, and promotes GluA2 endocytosis.
“Phosphorylation of GluA2 S880 prevents GRIP1/2 binding and promotes the interaction of the GluA2 PDZ ligand with PICK1 (Seidenman et al., 2003, Chung et al., 2000, Steinberg et al., 2006), destabilizing GluA2 within the PSD and promoting GluA2 endocytosis.”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Chung et al., 2000
The binding-results section shows that Ser880 phosphorylation prevents GluR2 (GluA2) binding to GRIP1 while preserving binding to PICK1; it does not show increased PICK1 binding or test GRIP2. The Discussion and the section on PKC-induced internalization report increased GluR2 internalization alongside Ser880 phosphorylation, but do not establish that phosphorylation itself destabilizes GluR2 within the PSD or causes endocytosis. Page numbers were not available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredGluA2 is required for the expression of cerebellar LTD.
“Several studies have demonstrated that GluA2 is required for the expression of cerebellar LTD.”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Chung et al., 2000
The Discussion says Purkinje-cell AMPA receptors contain GluR2 (GluA2) and that cerebellar LTD may involve AMPA-receptor endocytosis. It does not establish that GluA2 is required for the expression of cerebellar LTD; the paper’s GluR2 experiments concern receptor phosphorylation and internalization, not a test of that requirement. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe GluA2 S880 phosphorylation site is important in hippocampal LTD.
“The GluA2 S880 phosphorylation site has also been shown to be important in hippocampal LTD (Seidenman et al., 2003, Chung et al., 2000, Steinberg et al., 2006).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Chung et al., 2000
The Discussion links hippocampal LTD to PKC activation and suggests that GluR2 Ser880 phosphorylation may regulate AMPA-receptor internalization during synaptic plasticity. It does not show that the site is important for hippocampal LTD; that specific role remains a proposed connection in this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDephosphorylation of GluA2 S880 and Y876 enhances the interaction of GluA2 with GRIP1/2 scaffold proteins.
“Dephosphorylation of these two sites enhances the interaction of GluA2 with GRIP1/2 scaffold proteins (Hayashi and Huganir, 2004, Chung et al., 2000).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Chung et al., 2000
In “Phosphorylation of GluR2 PDZ ligand differentially regulates its interaction with GRIP1 and PICK1” (page unavailable), dephosphorylating the Ser880-phosphorylated GluR2 peptide restored GRIP1 binding. The passages do not establish that dephosphorylation of Y876 enhances binding or that the effect applies to GRIP2. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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- Authors
- Chung, H. J., Xia, J., Scannevin, R. H., Zhang, X., & Huganir, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-10-01
- Volume
- 20
- Issue
- 19
- Pages
- 7258-7267
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6772789
- OpenAlex
- W1929828037
- Cited by
- 558
- References
- 0
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 14 · 2020: 19 · 2019: 10 · 2018: 25 · 2017: 16 · 2016: 19 · 2015: 22 · 2014: 14 · 2013: 21 · 2012: 22
- FWCI
- 13.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- 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
- AMPA receptors, GluR2 subunit, PKC phosphorylation, PICK1, GRIP1, PSD-95, synaptic plasticity, receptor internalization, excitatory synapses, hippocampal neurons, dendrites
- MeSH terms
- Animals, Carrier Proteins, Cells, Cultured, Cytoskeletal Proteins, Humans, Kidney, Ligands, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Nuclear Proteins, Phosphorylation, Protein Kinase C, Serine, Tetradecanoylphorbol Acetate, Transcription Factors, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Receptors, AMPA, Two-Hybrid System Techniques, Rats, Nuclear Receptor Coactivator 2
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