---
_id: '10763'
abstract:
- lang: eng
  text: "AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission
    at excitatory\r\nsynapses in the brain. Glutamate binding to the receptor’s ligand-binding
    domains (LBDs)\r\nleads to ion channel activation and desensitization. Gating
    kinetics shape synaptic transmission\r\nand are strongly modulated by transmembrane
    AMPAR regulatory proteins (TARPs)\r\nthrough currently incompletely resolved mechanisms.
    Here, electron cryo-microscopy\r\nstructures of the GluA1/2 TARP-γ8 complex, in
    both open and desensitized states\r\n(at 3.5 Å), reveal state-selective engagement
    of the LBDs by the large TARP-γ8 loop (‘β1’),\r\nelucidating how this TARP stabilizes
    specific gating states. We further show how TARPs alter\r\nchannel rectification,
    by interacting with the pore helix of the selectivity filter. Lastly, we\r\nreveal
    that the Q/R-editing site couples the channel constriction at the filter entrance
    to the\r\ngate, and forms the major cation binding site in the conduction path.
    Our results provide a\r\nmechanistic framework of how TARPs modulate AMPAR gating
    and conductance."
acknowledgement: "We thank Ondrej Cais for critical reading of the manuscript. We
  are grateful to LMB\r\nscientific computing and the EM facility for support, Paul
  Emsley for help with model\r\nbuilding and Takanori Nakane for helpful comments
  with Relion 3.1. This work was\r\nsupported by grants from the Medical Research
  Council (MC_U105174197) and BBSRC\r\n(BB/N002113/1) to I.H.G, and grants from the
  MCIN/AEI/ 10.13039/501100011033 and\r\n“ESF Investing in your future” to B.H (PID2019-106284GA-I00
  and RYC2018-025720-I)."
article_number: '734'
article_processing_charge: No
article_type: original
author:
- first_name: Beatriz
  full_name: Herguedas, Beatriz
  last_name: Herguedas
- first_name: Bianka K.
  full_name: Kohegyi, Bianka K.
  last_name: Kohegyi
- first_name: Jan Niklas
  full_name: Dohrke, Jan Niklas
  last_name: Dohrke
- first_name: Jake
  full_name: Watson, Jake
  id: 63836096-4690-11EA-BD4E-32803DDC885E
  last_name: Watson
  orcid: 0000-0002-8698-3823
- first_name: Danyang
  full_name: Zhang, Danyang
  last_name: Zhang
- first_name: Hinze
  full_name: Ho, Hinze
  last_name: Ho
- first_name: Saher A.
  full_name: Shaikh, Saher A.
  last_name: Shaikh
- first_name: Remigijus
  full_name: Lape, Remigijus
  last_name: Lape
- first_name: James M.
  full_name: Krieger, James M.
  last_name: Krieger
- first_name: Ingo H.
  full_name: Greger, Ingo H.
  last_name: Greger
citation:
  ama: Herguedas B, Kohegyi BK, Dohrke JN, et al. Mechanisms underlying TARP modulation
    of the GluA1/2-γ8 AMPA receptor. <i>Nature Communications</i>. 2022;13. doi:<a
    href="https://doi.org/10.1038/s41467-022-28404-7">10.1038/s41467-022-28404-7</a>
  apa: Herguedas, B., Kohegyi, B. K., Dohrke, J. N., Watson, J., Zhang, D., Ho, H.,
    … Greger, I. H. (2022). Mechanisms underlying TARP modulation of the GluA1/2-γ8
    AMPA receptor. <i>Nature Communications</i>. Springer Nature. <a href="https://doi.org/10.1038/s41467-022-28404-7">https://doi.org/10.1038/s41467-022-28404-7</a>
  chicago: Herguedas, Beatriz, Bianka K. Kohegyi, Jan Niklas Dohrke, Jake Watson,
    Danyang Zhang, Hinze Ho, Saher A. Shaikh, Remigijus Lape, James M. Krieger, and
    Ingo H. Greger. “Mechanisms Underlying TARP Modulation of the GluA1/2-Γ8 AMPA
    Receptor.” <i>Nature Communications</i>. Springer Nature, 2022. <a href="https://doi.org/10.1038/s41467-022-28404-7">https://doi.org/10.1038/s41467-022-28404-7</a>.
  ieee: B. Herguedas <i>et al.</i>, “Mechanisms underlying TARP modulation of the
    GluA1/2-γ8 AMPA receptor,” <i>Nature Communications</i>, vol. 13. Springer Nature,
    2022.
  ista: Herguedas B, Kohegyi BK, Dohrke JN, Watson J, Zhang D, Ho H, Shaikh SA, Lape
    R, Krieger JM, Greger IH. 2022. Mechanisms underlying TARP modulation of the GluA1/2-γ8
    AMPA receptor. Nature Communications. 13, 734.
  mla: Herguedas, Beatriz, et al. “Mechanisms Underlying TARP Modulation of the GluA1/2-Γ8
    AMPA Receptor.” <i>Nature Communications</i>, vol. 13, 734, Springer Nature, 2022,
    doi:<a href="https://doi.org/10.1038/s41467-022-28404-7">10.1038/s41467-022-28404-7</a>.
  short: B. Herguedas, B.K. Kohegyi, J.N. Dohrke, J. Watson, D. Zhang, H. Ho, S.A.
    Shaikh, R. Lape, J.M. Krieger, I.H. Greger, Nature Communications 13 (2022).
date_created: 2022-02-20T23:01:30Z
date_published: 2022-02-08T00:00:00Z
date_updated: 2026-04-02T12:14:43Z
day: '08'
ddc:
- '570'
department:
- _id: PeJo
doi: 10.1038/s41467-022-28404-7
external_id:
  isi:
  - '000757297200008'
  pmid:
  - '35136046'
file:
- access_level: open_access
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  content_type: application/pdf
  creator: dernst
  date_created: 2022-02-21T07:59:32Z
  date_updated: 2022-02-21T07:59:32Z
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  file_name: 2022_NatureCommunications_Herguedas.pdf
  file_size: 2625540
  relation: main_file
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file_date_updated: 2022-02-21T07:59:32Z
has_accepted_license: '1'
intvolume: '        13'
isi: 1
language:
- iso: eng
month: '02'
oa: 1
oa_version: Published Version
pmid: 1
publication: Nature Communications
publication_identifier:
  eissn:
  - 2041-1723
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: ba8df636-2132-11f1-aed0-ed93e2281fdd
volume: 13
year: '2022'
...