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Cited by 347Neuroscience and Neuropharmacology ResearchReceptor Mechanisms and SignalingGenetics and Neurodevelopmental Disorders

Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation

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Lin, Da-Ting, Makino, Yuichi, Sharma, Kamal, Hayashi, Takashi, Neve, Rachael, Takamiya, Kogo, Huganir, Richard L·2009·Nature Neuroscience
DOI 10.1038/nn.2351PMC PMC2712131
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Abstract

The insertion of AMPA receptors (AMPARs) into the plasma membrane is an important step in the synaptic delivery of AMPARs during the expression of synaptic plasticity. However, the molecular mechanisms regulating AMPAR insertion remain elusive. By directly visualizing individual insertion events of the AMPAR subunit GluR1 in rodents, we found that the protein 4.1N was required for activity-dependent GluR1 insertion. Protein kinase C (PKC) phosphorylation of the serine 816 (S816) and S818 residues of GluR1 enhanced 4.1N binding to GluR1 and facilitated GluR1 insertion. In addition, palmitoylation of GluR1 C811 residue modulated PKC phosphorylation and GluR1 insertion. Finally, disrupting 4.1N-dependent GluR1 insertion decreased surface expression of GluR1 and the expression of long-term potentiation. Our study uncovers a previously unknown mechanism that governs activity-dependent GluR1 trafficking, reveals an interaction between AMPAR palmitoylation and phosphorylation, and underscores the functional importance of 4.1N in AMPAR trafficking and synaptic plasticity.

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  • By tagging AMPARs with a pH-sensitive tag (SEP-GluA1), insertion of AMPARs into the surface membrane can be directly visualized during LTP-inducing protocols.

    “By tagging AMPARs with a pH-sensitive tag (SEP-GluA1), the insertion of AMPARs into the surface membrane can be directly visualized during LTP-inducing protocols (249, 250, 335, 337, 338, 340).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [340]

    The Results section, “Capturing insertion events of GluRs” (page unavailable), reports direct visualization of surface GluR1 insertion using a pH-sensitive pHluorin tag. However, the paper describes LTP induction in separate whole-cell recordings, not visualization of insertion during an LTP-inducing protocol; the Discussion attributes that latter observation to another study. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • GluA1 directly interacts with the cytoskeletal scaffold protein 4.1N through the C-terminal juxtamembrane region, and this interaction promotes activity-dependent exocytosis of GluA1 from intracellular endosomes.

    “GluA1 directly interacts with the cytoskeletal scaffold protein 4.1N through the C-terminal juxtamembrane region, and this interaction promotes activity-dependent exocytosis of GluA1 from intracellular endosomes (Lin et al., 2009, Anggono and Huganir, 2012).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Lin et al., 2009

    The Introduction and Results describe 4.1N binding to the membrane-proximal region of GluR1 (GluA1) and its role in activity-dependent insertion at the extrasynaptic surface. The Introduction says AMPARs are *thought* to originate from recycling endosomes, but the paper does not establish that the 4.1N-dependent GluR1 insertion events specifically come from intracellular endosomes. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • During hippocampal LTP, PKC is activated to increase GluA1 S818 phosphorylation; peptide mimicking phospho-GluA1 S818 or shRNA-mediated knock-down of 4.1N both lead to decay of hippocampal LTP back to baseline, suggesting PKC/4.1N mediated increase in GluA1 exocytosis is necessary to maintain LTP.

    “During hippocampal LTP, PKC is activated to increase GluA1 S818 phosphorylation and a peptide mimicking phospho-GluA1 S818 or shRNA-mediated knock-down of 4.1N both lead to decay of hippocampal LTP back to baseline, suggesting that the PKC/4.1N mediated increase in GluA1 exocytosis is necessary to maintain LTP (Lin et al., 2009, Boehm et al., 2006).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Lin et al., 2009

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Large packets of GluA1 are inserted into the dendritic shaft from intracellular recycling endosomes, containing an estimated fifty GluA1-containing receptors, in an activity-dependent manner.

    “Large packets of GluA1 are inserted into the dendritic shaft from intracellular recycling endosomes, containing an estimated fifty GluA1-containing receptors, in an activity-dependent manner (Lin et al., 2009, Makino and Malinow, 2009).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Lin et al., 2009

    The Results (Capturing insertion events of GluRs; page unavailable) report GluR1 insertion in dendritic shafts, and activity suppression reduced its frequency. The Introduction says AMPARs are thought to originate from recycling endosomes, but the paper does not establish that the observed GluR1 packets came from them or estimate fifty receptors per packet; it instead describes vesicles as likely containing a limited number of receptors. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Surface localized AMPARs are supplied by exocytosis from pools of intracellular receptors contained within endosomes.

    “Surface localized AMPARs are supplied by exocytosis from pools of intracellular receptors contained within endosomes (Lin et al., 2009, Makino and Malinow, 2009).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Lin et al., 2009

    The Introduction says AMPARs delivered during LTP are thought to originate from recycling endosomes, and the Results and Discussion describe vesicle insertion at the neuronal surface. The source supports the proposed route but does not establish endosomes as the source of surface AMPARs generally; the claim states that origin without the paper’s qualification. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Lin, D.-T., Makino, Y., Sharma, K., Hayashi, T., Neve, R., Takamiya, K., & Huganir, R. L.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Massachusetts Institute of Technology (US)
  • University of Miyazaki (JP)
Corresponding author
Huganir, Richard L
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2009-06-07
Volume
12
Issue
7
Pages
879-887
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2351
PMC
PMC2712131
OpenAlex
W2034502353
Cited by
347
References
7
Citations by year
2026: 7 · 2025: 10 · 2024: 8 · 2023: 17 · 2022: 14 · 2021: 20 · 2020: 24 · 2019: 16 · 2018: 22 · 2017: 18 · 2016: 21 · 2015: 17 · 2014: 26 · 2013: 37 · 2012: 26
FWCI
12.61
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • Howard Hughes Medical Institute
  • Johns Hopkins University
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS036715)
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 › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
AMPA receptors, GluR1, palmitoylation, protein phosphorylation, protein kinase C, long-term potentiation, synaptic plasticity
MeSH terms
Animals, Cell Membrane, Cells, Cultured, Cytoskeletal Proteins, Hippocampus, Membrane Proteins, Mice, Inbred C57BL, Microscopy, Fluorescence, Mutation, Neurons, Neuropeptides, Phosphorylation, Protein Kinase C, Video Recording, Long-Term Potentiation, Receptors, AMPA, Mice, Rats, Lipoylation, In Vitro Techniques

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