Synaptic Accumulation of PSD-95 and Synaptic Function Regulated by Phosphorylation of Serine-295 of PSD-95
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The scaffold protein PSD-95 promotes the maturation and strengthening of excitatory synapses, functions that require proper localization of PSD-95 in the postsynaptic density (PSD). Here we report that phosphorylation of ser-295 enhances the synaptic accumulation of PSD-95 and the ability of PSD-95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. We present evidence that a Rac1-JNK1 signaling pathway mediates ser-295 phosphorylation and regulates synaptic content of PSD-95. Ser-295 phosphorylation is suppressed by chronic elevation, and increased by chronic silencing, of synaptic activity. Rapid dephosphorylation of ser-295 occurs in response to NMDA treatment that causes chemical long-term depression (LTD). Overexpression of a phosphomimicking mutant (S295D) of PSD-95 inhibited NMDA-induced AMPA receptor internalization and blocked the induction of LTD. The data suggest that synaptic strength can be regulated by phosphorylation-dephosphorylation of ser-295 of PSD-95 and that synaptic depression requires the dephosphorylation of ser-295.
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NMDA-cLTD activation of CaN and PP1/2A negatively regulates PSD-95 postsynaptic clustering and binding to Stargazin to promote AMPAR removal.
“In particular, NMDA-cLTD activation of CaN and PP1/2A negatively regulates PSD-95 postsynaptic clustering and binding to Stargazin to promote AMPAR removal”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Kim et al., 2007
GluA1 phosphorylation directly regulates trafficking, but there are other phosphatase substrates, including PSD-95 and Stargazin, that are also involved in synaptic AMPAR removal during LTD.
“GluA1 phosphorylation directly regulates trafficking, but there are other phosphatase substrates, including PSD-95 and Stargazin, that are also involved in synaptic AMPAR removal during LTD.”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Kim et al., 2007
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“In particular, NMDA-cLTD activation of CaN and PP1/2A negatively regulates PSD-95 postsynaptic clustering and binding to Stargazin to promote AMPAR removal (Colledge et al., 2003; Tomita et al., 2005; Kim et al., 2007; Opazo et al., 2010).”
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- Authors
- Kim, M. J., Futai, K., Jo, J., Hayashi, Y., Cho, K., & Sheng, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Bristol (GB)
- Corresponding author
- Sheng, Morgan
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 56
- Issue
- 3
- Pages
- 488-502
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2003931473
- Cited by
- 278
- References
- 35
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 9 · 2023: 9 · 2022: 18 · 2021: 15 · 2020: 17 · 2019: 15 · 2018: 16 · 2017: 19 · 2016: 17 · 2015: 12 · 2014: 15 · 2013: 19 · 2012: 13
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Update notices
- erratum (2008-01-24)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BB/D013232/2)
- RIKEN
- National Institute of Mental Health (R01MH076936, MH076936)
- National Institute on Drug Abuse (DA017310)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- PSD-95, postsynaptic density, excitatory postsynaptic currents, Rac1, JNK1, synaptic plasticity, long-term depression, NMDA, AMPA receptor internalization, scaffold proteins
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Animals, Newborn, Cells, Cultured, Hippocampus, Membrane Proteins, Mutation, Synaptic Transmission, Organ Culture Techniques, Phosphorylation, Serine, Synaptic Membranes, Signal Transduction, N-Methylaspartate, Receptors, AMPA, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, rac1 GTP-Binding Protein, Long-Term Synaptic Depression, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Rats
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