CoChat
Sign Up
Cited by 18Neuroscience and Neuropharmacology ResearchCellular transport and secretionExtracellular vesicles in disease

Molecular Characterization of AMPA-Receptor-Containing Vesicles

Open access
Peters, John Jacob, Leitz, Jeremy, Oses-Prieto, Juan A., Burlingame, Alma L., Brunger, Axel T.·2021·Frontiers in Molecular Neuroscience
DOI 10.3389/fnmol.2021.754631PMC PMC8554035

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Regulated delivery of AMPA receptors (AMPARs) to the postsynaptic membrane is an essential step in synaptic strength modification, and in particular, long-term potentiation (LTP). While LTP has been extensively studied using electrophysiology and light microscopy, several questions regarding the molecular mechanisms of AMPAR delivery via trafficking vesicles remain outstanding, including the gross molecular make up of AMPAR trafficking organelles and identification and location of calcium sensors required for SNARE complex-dependent membrane fusion of such trafficking vesicles with the plasma membrane. Here, we isolated AMPA-containing vesicles (ACVs) from whole mouse brains via immunoisolation and characterized them using immunoelectron microscopy, immunoblotting, and liquid chromatography–tandem mass spectrometry (LC–MS/MS). We identified several proteins on ACVs that were previously found to play a role in AMPAR trafficking, including synaptobrevin-2, Rabs, the SM protein Munc18-1, the calcium-sensor synaptotagmin-1, as well as several new candidates, including synaptophysin and synaptogyrin on ACV membranes. Additionally, we identified two populations of ACVs based on size and molecular composition: small-diameter, synaptobrevin-2- and GluA1-containing ACVs, and larger transferrin- receptor-, GluA1-, GluA2-, and GluA3-containing ACVs. The small-diameter population of ACVs may represent a fusion-capable population of vesicles due to the presence of synaptobrevin-2. Because the fusion of ACVs may be a requisite of LTP, this population could represent trafficking vesicles related to LTP.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fnmol.2021.754631

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • AMPAR-containing vesicles are associated with synaptotagmin-1, which is involved in LTP.

    “Additional support for the vesicle-centric model is the finding that AMPAR-containing vesicles (obtained by immunoisolation) are associated with such proteins as synaptotagmin-1 (341), which is involved in LTP (195).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [341]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 58

  1. Ahmed S. Holt M. Riedel D. Jahn R. (2013). Small-scale isolation of synaptic vesicles from mammalian brain. Nat. Protoco. 8 998– 1009. 10.1038/nprot.2013.053 23619891 · DOI
  2. Bredt D. S. Nicoll R. A. (2003). AMPA receptor trafficking at excitatory synapses. Neuron 40 361– 379. 14556714
  3. Brown T. C. Correia S. S. Petrok C. N. Esteban J. A. (2007). Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation. J. Neurosci. 27 13311– 13315. 10.1523/JNEUROSCI.4258-07.2007 18045925 PMC6673392 · DOI
  4. Brown T. C. Tran I. C. Backos D. S. Esteban J. A. (2005). NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45 81– 94. 10.1016/j.neuron.2004.12.023 15629704 · DOI
  5. Brunger A. T. Choi U. B. Lai Y. Leitz J. White K. I. Zhou Q. (2019). The pre-synaptic fusion machinery. Curr. Opin. Struct. Biol. 54 179– 188. 10.1016/j.sbi.2019.03.007 30986753 PMC6939388 · DOI
  6. Chen H.-J. Anagnostou G. Chai A. Withers J. Morris A. Adhikaree J. (2010). Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J. Biol. Chem. 285 40266– 40281. 10.1074/jbc.M110.161398 20940299 PMC3001007 · DOI
  7. Choquet D. Hosy E. (2020). AMPA receptor nanoscale dynamic organization and synaptic plasticities. Curr. Opin. Neurobiol. 63 137– 145. 10.1016/j.conb.2020.04.003 32416471 · DOI
  8. Clauser K. R. Baker P. Burlingame A. L. (1999). Role of accurate mass measurement (±10 ppm) in protein identification strategies employing MS or MS/MS and database searching. Anal. Chem. 71 2871– 2882. 10.1021/ac9810516 10424174 · DOI
  9. Collingridge G. L. Isaac J. T. R. Wang Y. T. (2004). Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5 952– 962. 10.1038/nrn1556 15550950 · DOI · Paper page
  10. Corera A. T. Doucet G. Fon E. A. (2009). Long-Term potentiation in isolated dendritic spines. PLoS One 4: e6021. 10.1371/journal.pone.0006021 19547754 PMC2695539 · DOI
  11. Craven S. E. Bredt D. S. (1998). PDZ proteins organize synaptic signaling pathways. Cell 93 495– 498. 10.1016/S0092-8674(00)81179-4 9604925 · DOI
  12. Dingledine R. Borges K. Bowie D. Traynelis S. F. (1999). The glutamate receptor ion channels. Pharmacol. Rev. 51 7– 61. 10049997
  13. Esteves da Silva M. Adrian M. Schätzle P. Lipka J. Watanabe T. Cho S. (2015). Positioning of AMPA receptor-containing endosomes regulates synapse architecture. Cell Rep. 13 933– 943. 10.1016/j.celrep.2015.09.062 26565907 · DOI
  14. Fenyö D. Beavis R. C. (2003). A method for assessing the statistical significance of mass spectrometry-based protein identifications using general scoring schemes. Anal. Chem. 75 768– 774. 10.1021/ac0258709 12622365 · DOI
  15. Gan M. Jiang P. McLean P. Kanekiyo T. Bu G. (2014). Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) regulates the stability and function of glua1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in neurons. PLoS One 9: e113237. 10.1371/journal.pone.0113237 25500815 PMC4264746 · DOI
  16. Gerges N. Z. Backos D. S. Esteban J. A. (2004). Local Control of AMPA receptor trafficking at the postsynaptic terminal by a small GTPase of the rab family. J. Biol. Chem. 279 43870– 43878. 10.1074/jbc.M404982200 15297461 · DOI
  17. Griffiths G. Hoflack B. Simons K. Mellman I. Kornfeld S. (1988). The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell 52 329– 341. 10.1016/S0092-8674(88)80026-6 2964276 · DOI
  18. Guan S. Price J. C. Prusiner S. B. Ghaemmaghami S. Burlingame A. L. (2011). A data processing pipeline for mammalian proteome dynamics studies using stable isotope metabolic labeling. Mol. Cell. Proteomics 10: M111.010728. 10.1074/mcp.M111.010728 21937731 PMC3237081 · DOI
  19. Hanson P. I. Roth R. Morisaki H. Jahn R. Heuser J. E. (1997). Structure and conformational changes in nsf and its membrane receptor complexes visualized by quick-freeze/deep-etch electron microscopy. Cell 90 523– 535. 10.1016/S0092-8674(00)80512-7 9267032 · DOI
  20. Hata Y. Südhof T. C. (1995). A novel ubiquitous form of munc-18 interacts with multiple syntaxins: use of the yeast two-hybrid system to study interactions between proteins involved in membrane. J. Biol. Chem. 270 13022– 13028. 10.1074/jbc.270.22.13022 7768895 · DOI
  21. Hoogenraad C. C. Popa I. Futai K. Sanchez-Martinez E. Wulf P. S. van Vlijmen T. (2010). Neuron specific rab4 effector GRASP-1 coordinates membrane specialization and maturation of recycling endosomes. PLoS Biol. 8: e1000283. 10.1371/journal.pbio.1000283 20098723 PMC2808209 · DOI
  22. Janz R. Südhof T. C. Hammer R. E. Unni V. Siegelbaum S. A. Bolshakov V. Y. (1999). Essential roles in synaptic plasticity for Synaptogyrin I and Synaptophysin I. Neuron 24 687– 700. 10.1016/S0896-6273(00)81122-8 10595519 · DOI
  23. Jiang C.-H. Wei M. Zhang C. Shi Y. S. (2021). The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65. Proc. Natl. Acad. Sci. U.S.A. 118: e2019194118. 10.1073/pnas.2019194118 33627404 PMC7936340 · DOI
  24. Ju W. Morishita W. Tsui J. Gaietta G. Deerinck T. J. Adams S. R. (2004). Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors. Nat. Neurosci. 7 244– 253. 14770185
  25. Jurado S. Goswami D. Zhang Y. Molina A. J. M. Südhof T. C. Malenka R. C. (2013). LTP requires a unique postsynaptic SNARE fusion machinery. Neuron 77 542– 558. 10.1016/j.neuron.2012.11.029 23395379 PMC3569727 · DOI · Paper page
  26. Kittler J. T. Moss S. J. (eds) (2006). The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. Boca Raton, FL: CRC Press/Taylor & Francis. 21204469
  27. Lai Y. Choi U. B. Leitz J. Rhee H. J. Lee C. Altas B. (2017). Molecular mechanisms of synaptic vesicle priming by Munc13 and Munc18. Neuron 95 591.e– 607.e. 10.1016/j.neuron.2017.07.004 28772123 PMC5747255 · DOI
  28. Largo-Barrientos P. Apóstolo N. Creemers E. Callaerts-Vegh Z. Swerts J. Davies C. (2021). Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation. Neuron 109 767.e– 777.e. 10.1016/j.neuron.2020.12.016 33472038 PMC7927913 · DOI
  29. Liu K. Lei R. Li Q. Wang X.-X. Wu Q. An P. (2016). Transferrin receptor controls AMPA receptor trafficking efficiency and synaptic plasticity. Sci. Rep. 6: 21019. 10.1038/srep21019 26880306 PMC4754636 · DOI
  30. Liu S.-Q. J. Cull-Candy S. G. (2000). Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405 454– 458. 10.1038/35013064 10839540 · DOI
  31. Lledo P.-M. Zhang X. Südhof T. C. Malenka R. C. Nicoll R. A. (1998). Postsynaptic membrane fusion and long-term potentiation. Science 279 399– 403. 10.1126/science.279.5349.399 9430593 · DOI · Paper page
  32. Lu W. Shi Y. Jackson A. C. Bjorgan K. During M. J. Sprengel R. (2009). Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62 254– 268. 10.1016/j.neuron.2009.02.027 19409270 PMC3632349 · DOI · Paper page
  33. Ma C. Su L. Seven A. B. Xu Y. Rizo J. (2013). Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science 339 421– 425. 10.1126/science.1230473 23258414 PMC3733786 · DOI
  34. Malinow R. Malenka R. C. (2002). AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25 103– 126. 10.1146/annurev.neuro.25.112701.142758 12052905 · DOI · Paper page
  35. Mayer A. Wickner W. Haas A. (1996). Sec18p (NSF)-driven release of sec17p (α-SNAP) can precede docking and fusion of yeast vacuoles. Cell 85 83– 94. 10.1016/S0092-8674(00)81084-3 8620540 · DOI
  36. Mignogna M. L. Giannandrea M. Gurgone A. Fanelli F. Raimondi F. Mapelli L. (2015). The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition. Nat. Commun. 6: 6504. 10.1038/ncomms7504 25784538 PMC4383008 · DOI
  37. Munro S. (2011). The golgin coiled-coil proteins of the golgi apparatus. Cold Spring Harb. Perspect. Biol. 3: a005256. 10.1101/cshperspect.a005256 21436057 PMC3098672 · DOI
  38. Nabavi S. Fox R. Proulx C. D. Lin J. Y. Tsien R. Y. Malinow R. (2014). Engineering a memory with LTD and LTP. Nature 511 348– 352. 10.1038/nature13294 24896183 PMC4210354 · DOI · Paper page
  39. Newpher T. M. Ehlers M. D. (2008). Glutamate receptor dynamics in dendritic microdomains. Neuron 58 472– 497. 10.1016/j.neuron.2008.04.030 18498731 PMC2572138 · DOI · Paper page
  40. Noel J. Ralph G. S. Pickard L. Williams J. Molnar E. Uney J. B. (1999). Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism. Neuron 23 365– 376. 10.1016/S0896-6273(00)80786-2 10399941 · DOI
  41. Pang Z. P. Sun J. Rizo J. Maximov A. Südhof T. C. (2006). Genetic analysis of synaptotagmin 2 in spontaneous and Ca2+-triggered neurotransmitter release. EMBO J. 25 2039– 2050. 10.1038/sj.emboj.7601103 16642042 PMC1462977 · DOI
  42. Paoletti P. Bellone C. Zhou Q. (2013). NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14 383– 400. 10.1038/nrn3504 23686171 · DOI · Paper page
  43. Perrett R. M. Alexopoulou Z. Tofaris G. K. (2015). The endosomal pathway in Parkinson’s disease. Mol. Cell. Neurosci. 66 21– 28. 10.1016/j.mcn.2015.02.009 25701813 · DOI
  44. Schwenk B. M. Hartmann H. Serdaroglu A. Schludi M. H. Hornburg D. Meissner F. (2016). TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. EMBO J. 35 2350– 2370. 10.15252/embj.201694221 27621269 PMC5090220 · DOI
  45. Schwenk J. Harmel N. Brechet A. Zolles G. Berkefeld H. Müller C. S. (2012). High-Resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes. Neuron 74 621– 633. 10.1016/j.neuron.2012.03.034 22632720 · DOI · Paper page
  46. Shanks N. F. Savas J. N. Maruo T. Cais O. Hirao A. Oe S. (2012). Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L. Cell Rep. 1 590– 598. 10.1016/j.celrep.2012.05.004 22813734 PMC3401968 · DOI
  47. Shepherd J. D. Huganir R. L. (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23 613– 643. 10.1146/annurev.cellbio.23.090506.123516 17506699 · DOI · Paper page
  48. Shi S.-H. Hayashi Y. Petralia R. S. Zaman S. H. Wenthold R. J. Svoboda K. (1999). Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284 1811– 1816. 10364548
  49. Söllner T. Bennett M. K. Whiteheart S. W. Scheller R. H. Rothman J. E. (1993). A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75 409– 418. 10.1016/0092-8674(93)90376-2 8221884 · DOI
  50. Sreedharan J. Blair I. P. Tripathi V. B. Hu X. Vance C. Rogelj B. (2008). TDP-43 Mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319 1668– 1672. 10.1126/science.1154584 18309045 PMC7116650 · DOI · Paper page
  51. Südhof T. C. (2013). Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80 675– 690. 10.1016/j.neuron.2013.10.022 24183019 PMC3866025 · DOI · Paper page
  52. Takamori S. Holt M. Stenius K. Lemke E. A. Gronborg M. Riedel D. (2006). Molecular anatomy of a trafficking organelle. Cell 127 831– 846. 10.1016/j.cell.2006.10.030 17110340 · DOI · Paper page
  53. Takumi Y. Ramírez-León V. Laake P. Rinvik E. Ottersen O. P. (1999). Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat. Neurosci. 2 618– 624. 10.1038/10172 10409387 · DOI · Paper page
  54. Vilariño-Güell C. Rajput A. Milnerwood A. J. Shah B. Szu-Tu C. Trinh J. (2014). DNAJC13 mutations in Parkinson disease. Hum. Mol. Genet. 23 1794– 1801. 10.1093/hmg/ddt570 24218364 PMC3999380 · DOI
  55. Wei M. Zhang J. Jia M. Yang C. Pan Y. Li S. (2016). α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors. Proc. Natl. Acad. Sci. U.S.A. 113 E2695– E2704. 10.1073/pnas.1524589113 27114538 PMC4868484 · DOI
  56. Wenthold R. J. Petralia R. S. Blahos J. I. I. Niedzielski A. S. (1996). Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J. Neurosci. 16 1982– 1989. 10.1523/JNEUROSCI.16-06-01982.1996 8604042 PMC6578515 · DOI · Paper page
  57. Zamanillo D. Sprengel R. Hvalby Ø Jensen V. Burnashev N. Rozov A. (1999). Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284 1805– 1811. 10.1126/science.284.5421.1805 10364547 · DOI · Paper page
  58. Zhao Y. Chen S. Swensen A. C. Qian W.-J. Gouaux E. (2019). Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM. Science 364 355– 362. 10.1126/science.aaw8250 30975770 PMC6701862 · DOI

Cited by

Sorted by citations

  • Synaptic memory and CaMKII

    Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works

    “Additional support for the vesicle-centric model is the fi nding that AMPAR-con-taining vesicles (obtained by immunoisolation) are associated with such proteins as synaptotagmin-1 (341), which is involved in LTP (195).”
    Background

Authors
Peters, J. J., Leitz, J., Oses-Prieto, J. A., Burlingame, A. L., & Brunger, A. T.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of California, San Francisco (US)
ORCID
Venue
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Published
2021-10-15
Volume
14
Pages
754631-754631
ISSN
1662-5099 (ISSN-L)
DOI
10.3389/fnmol.2021.754631
PMC
PMC8554035
OpenAlex
W3207832613
Cited by
18
References
6
Citations by year
2026: 5 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 3
FWCI
1.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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 › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
AMPA receptors, vesicle trafficking, long-term potentiation, synaptobrevin 2, synaptotagmin-1, Munc18-1, Rab, synaptophysin, calcium sensor, SNARE complex, membrane fusion, GluR1, GluA2, GluA3, transferrin receptor, postsynaptic membrane

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review