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Cited by 132Neuroscience and Neuropharmacology ResearchUbiquitin and proteasome pathwaysCellular transport and secretion

Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation

Open access
Widagdo, Jocelyn, Chai, Ye Jin, Ridder, Margreet C., Chau, Yu Qian, Johnson, Richard C., Sah, Pankaj, Huganir, Richard L., Anggono, Victor·2015·Cell Reports
DOI 10.1016/j.celrep.2015.01.015PMC PMC4524782
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Abstract

AMPA receptors (AMPARs) have recently been shown to undergo post-translational ubiquitination in mammalian neurons. However, the underlying molecular mechanisms are poorly understood and remain controversial. Here, we report that all four AMPAR subunits (GluA1-4) are rapidly ubiquitinated upon brief application of AMPA or bicuculline in cultured neurons. This process is Ca 2+ dependent and requires the activity of L-type voltage-gated Ca 2+ channels and Ca 2+ /calmodulin-dependent kinase II. The ubiquitination of all subunits occurs exclusively on AMPARs located on the plasma membrane post-endocytosis. The sites of ubiquitination were mapped to Lys-868 in GluA1 and Lys-870/Lys-882 in GluA2 C-terminals. Mutation of these lysines did not affect basal surface expression or AMPA-induced internalization of GluA1 and GluA2 subunits. Instead, it reduced the intracellular trafficking of AMPARs to the late endosomes and thus protein degradation. These data indicate that ubiquitination is an important regulatory signal for controlling AMPAR function, which may be crucial for synaptic plasticity.

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  • Bicuculline treatment stimulates GluA2 ubiquitination on K882, and AMPAR ubiquitination has been shown to be required for homeostatic scaling-down.

    “Bicuculline treatment stimulates GluA2 ubiquitination on K882 (Widagdo et al., 2015), very close to the Y876 and S880 phosphorylation sites, and AMPAR ubiquitination has been shown to be required for homeostatic scaling-down (Scudder et al., 2014).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Widagdo et al., 2015

    The Results section reports that bicuculline induces ubiquitination of GluA2, and a separate Results section identifies K882 as a major GluA2 ubiquitination site. However, the K882 mapping used AMPA treatment, not bicuculline, so the paper does not establish that bicuculline stimulates ubiquitination specifically at K882. The scaling-down statement is cited to Scudder et al., not to Widagdo et al. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • All four AMPAR subunits are ubiquitinated, with major sites on GluA1 and GluA2 mapped to GluA1 K868 and GluA2 K870/K882.

    “All four AMPAR subunit are also ubiquitinated. The major sites of ubiquitination on GluA1 and GluA2 have been mapped to GluA1 K868 and GluA2 K870/K882 (Widagdo et al., 2015, Widagdo et al., 2017, Lussier et al., 2015).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Widagdo et al., 2015

  • GluA2 is ubiquitinated on K870 and K882 in response to neuronal activity, and this is dependent on AMPAR internalization.

    “GluA2 is also a target of ubiquitination on K870 and K882, which occurs in response to neuronal activity and is dependent on AMPAR internalization (Widagdo et al., 2015).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Widagdo et al., 2015

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Research works printed but not linked: 27

  1. Anggono V Koç-Schmitz Y Widagdo J Kormann J Quan A Chen CM Robinson PJ Choi SY Linden DJ Plomann M Huganir RL 2013 PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression Proc Natl Acad Sci USA 110 13976 13981 23918399 PMC3752261
  2. Burbea M Dreier L Dittman JS Grunwald ME Kaplan JM 2002 Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans Neuron 35 107 120 12123612
  3. Cajigas IJ Will T Schuman EM 2010 Protein homeostasis and synaptic plasticity EMBO J 29 2746 2752 20717144 PMC2924649
  4. Carroll RC Beattie EC Xia H Lüscher C Altschuler Y Nicoll RA Malenka RC von Zastrow M 1999 Dynamin-dependent endocytosis of ionotropic glutamate receptors Proc Natl Acad Sci USA 96 14112 14117 10570207 PMC24199
  5. Ehlers MD 2000 Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting Neuron 28 511 525 11144360
  6. Fu AK Hung KW Fu WY Shen C Chen Y Xia J Lai KO Ip NY 2011 APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity Nat Neurosci 14 181 189 21186356
  7. Govers R ten Broeke T van Kerkhof P Schwartz AL Strous GJ 1999 Identification of a novel ubiquitin conjugation motif, required for ligand-induced internalization of the growth hormone receptor EMBO J 18 28 36 9878047 PMC1171099
  8. Haglund K Dikic I 2005 Ubiquitylation and cell signaling EMBO J 24 3353 3359 16148945 PMC1276169
  9. Haugsten EM Malecki J Bjørklund SM Olsnes S Wesche J 2008 Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis Mol Biol Cell 19 3390 3403 18480409 PMC2488279
  10. Hell JW 2014 CaMKII: claiming center stage in postsynaptic function and organization Neuron 81 249 265 24462093 PMC4570830
  11. Hershko A Ciechanover A 1998 The ubiquitin system Annu Rev Biochem 67 425 479 9759494
  12. Hou Q Gilbert J Man HY 2011 Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation Neuron 72 806 818 22153376 PMC3240854
  13. Huang F Goh LK Sorkin A 2007 EGF receptor ubiquitination is not necessary for its internalization Proc Natl Acad Sci USA 104 16904 16909 17940017 PMC2040475
  14. Huganir RL Nicoll RA 2013 AMPARs and synaptic plasticity: the last 25 years Neuron 80 704 717 24183021 PMC4195488
  15. Lee SH Simonetta A Sheng M 2004 Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons Neuron 43 221 236 15260958
  16. Lin A Hou Q Jarzylo L Amato S Gilbert J Shang F Man HY 2011 Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking J Neurochem 119 27 39 21338354 PMC3110981
  17. Lu W Roche KW 2012 Posttranslational regulation of AMPA receptor trafficking and function Curr Opin Neurobiol 22 470 479 22000952 PMC3279598
  18. Lussier MP Nasu-Nishimura Y Roche KW 2011 Activity-dependent ubiquitination of the AMPA receptor subunit GluA2 J Neurosci 31 3077 3081 21414928 PMC3081723
  19. Lussier MP Herring BE Nasu-Nishimura Y Neutzner A Karbowski M Youle RJ Nicoll RA Roche KW 2012 Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission Proc Natl Acad Sci USA 109 19426 19431 23129617 PMC3511152
  20. Macia E Ehrlich M Massol R Boucrot E Brunner C Kirchhausen T 2006 Dynasore, a cell-permeable inhibitor of dynamin Dev Cell 10 839 850 16740485
  21. Nathan JA Kim HT Ting L Gygi SP Goldberg AL 2013 Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes? EMBO J 32 552 565 23314748 PMC3579138
  22. Patrick GN Bingol B Weld HA Schuman EM 2003 Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs Curr Biol 13 2073 2081 14653997
  23. Schwarz LA Hall BJ Patrick GN 2010 Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway J Neurosci 30 16718 16729 21148011 PMC3079366
  24. Shepherd JD Huganir RL 2007 The cell biology of synaptic plasticity: AMPA receptor trafficking Annu Rev Cell Dev Biol 23 613 643 17506699
  25. Sorkin A von Zastrow M 2009 Endocytosis and signalling: intertwining molecular networks Nat Rev Mol Cell Biol 10 609 622 19696798 PMC2895425
  26. Yuen EY Wei J Liu W Zhong P Li X Yan Z 2012 Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex Neuron 73 962 977 22405206 PMC3302010
  27. Zhang D Hou Q Wang M Lin A Jarzylo L Navis A Raissi A Liu F Man HY 2009 Na,K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis J Neurosci 29 4498 4511 19357275 PMC2680442

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Authors
Widagdo, J., Chai, Y. J., Ridder, M. C., Chau, Y. Q., Johnson, R. C., Sah, P., Huganir, R. L., & Anggono, V.
Affiliations
  • The University of Queensland (AU)
  • Johns Hopkins University (US)
Corresponding author
  • Huganir, Richard L.
  • Anggono, Victor
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2015-02
Volume
10
Issue
5
Pages
783-795
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2015.01.015
PMC
PMC4524782
OpenAlex
W2019147863
Cited by
132
References
4
Citations by year
2026: 4 · 2025: 5 · 2024: 22 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 13 · 2019: 7 · 2018: 12 · 2017: 16 · 2016: 10 · 2015: 10
FWCI
7.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Johns Hopkins University
  • John T. Reid Charitable Trusts
  • National Health and Medical Research Council
  • National Medical Research Council
  • 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 › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
AMPA receptors, GluR1, GluA2, ubiquitination, activity-dependent regulation, L-type calcium channels, CaMKII, receptor internalization, endocytosis, late endosomes, protein degradation, synaptic plasticity, post-translational modification

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