---
_id: '9549'
abstract:
- lang: eng
  text: 'AMPA receptors (AMPARs) mediate the majority of excitatory transmission in
    the brain and enable the synaptic plasticity that underlies learning1. A diverse
    array of AMPAR signalling complexes are established by receptor auxiliary subunits,
    which associate with the AMPAR in various combinations to modulate trafficking,
    gating and synaptic strength2. However, their mechanisms of action are poorly
    understood. Here we determine cryo-electron microscopy structures of the heteromeric
    GluA1–GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR
    complex in the forebrain, in both resting and active states. Two TARP-γ8 and two
    CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of
    the receptor, with site-specific lipids shaping each interaction and affecting
    the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry
    between GluA1 and GluA2 along the ion conduction path and an outward expansion
    of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting
    the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards
    the pore exit upon activation, extending their reach for cytoplasmic receptor
    elements. CNIH2 achieves this through its uniquely extended M2 helix, which has
    transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator
    that is capable of providing hippocampal pyramidal neurons with their integrative
    synaptic properties. '
acknowledgement: We thank members of the Greger laboratory, B. Herguedas, J. Krieger
  and J.-N. Dohrke for comments on the manuscript; J. Krieger and J.-N. Dohrke for
  discussion, J. Krieger for help with the normal mode analysis, B. Köhegyi for help
  with cryo-EM imaging, V. Chang and K. Suzuki for helping to generate the CNIH2-1D4-HA
  stable cell line, M. Carvalho for assistance at early stages of this project, the
  LMB scientific computing and the cryo-EM facility for support, P. Emsley for help
  with model building, T. Nakane for helpful comments with RELION 3.1 and R. Warshamanage
  for helping with EMDA cryo-EM-map processing. We acknowledge the Diamond Light Source
  for access and support of the Cryo-EM facilities at the UK national electron bio10
  imaging centre (eBIC), proposal EM17434, funded by the Wellcome Trust, MRC and BBSRC.
  This work was supported by grants from the Medical Research Council, as part of
  United Kingdom Research and Innovation (also known as UK Research and Innovation)
  (MC_U105174197) and BBSRC (BB/N002113/1) to I.H.G.
article_processing_charge: No
article_type: original
author:
- first_name: Danyang
  full_name: Zhang, Danyang
  last_name: Zhang
- first_name: Jake
  full_name: Watson, Jake
  id: 63836096-4690-11EA-BD4E-32803DDC885E
  last_name: Watson
  orcid: 0000-0002-8698-3823
- first_name: Peter M.
  full_name: Matthews, Peter M.
  last_name: Matthews
- first_name: Ondrej
  full_name: Cais, Ondrej
  last_name: Cais
- first_name: Ingo H.
  full_name: Greger, Ingo H.
  last_name: Greger
citation:
  ama: Zhang D, Watson J, Matthews PM, Cais O, Greger IH. Gating and modulation of
    a hetero-octameric AMPA glutamate receptor. <i>Nature</i>. 2021;594:454-458. doi:<a
    href="https://doi.org/10.1038/s41586-021-03613-0">10.1038/s41586-021-03613-0</a>
  apa: Zhang, D., Watson, J., Matthews, P. M., Cais, O., &#38; Greger, I. H. (2021).
    Gating and modulation of a hetero-octameric AMPA glutamate receptor. <i>Nature</i>.
    Springer Nature. <a href="https://doi.org/10.1038/s41586-021-03613-0">https://doi.org/10.1038/s41586-021-03613-0</a>
  chicago: Zhang, Danyang, Jake Watson, Peter M. Matthews, Ondrej Cais, and Ingo H.
    Greger. “Gating and Modulation of a Hetero-Octameric AMPA Glutamate Receptor.”
    <i>Nature</i>. Springer Nature, 2021. <a href="https://doi.org/10.1038/s41586-021-03613-0">https://doi.org/10.1038/s41586-021-03613-0</a>.
  ieee: D. Zhang, J. Watson, P. M. Matthews, O. Cais, and I. H. Greger, “Gating and
    modulation of a hetero-octameric AMPA glutamate receptor,” <i>Nature</i>, vol.
    594. Springer Nature, pp. 454–458, 2021.
  ista: Zhang D, Watson J, Matthews PM, Cais O, Greger IH. 2021. Gating and modulation
    of a hetero-octameric AMPA glutamate receptor. Nature. 594, 454–458.
  mla: Zhang, Danyang, et al. “Gating and Modulation of a Hetero-Octameric AMPA Glutamate
    Receptor.” <i>Nature</i>, vol. 594, Springer Nature, 2021, pp. 454–58, doi:<a
    href="https://doi.org/10.1038/s41586-021-03613-0">10.1038/s41586-021-03613-0</a>.
  short: D. Zhang, J. Watson, P.M. Matthews, O. Cais, I.H. Greger, Nature 594 (2021)
    454–458.
date_created: 2021-06-13T22:01:33Z
date_published: 2021-06-02T00:00:00Z
date_updated: 2026-06-18T19:54:04Z
day: '02'
ddc:
- '570'
department:
- _id: PeJo
doi: 10.1038/s41586-021-03613-0
external_id:
  isi:
  - '000657238100003'
  pmid:
  - '34079129'
fulldoi: https://doi.org/10.1038/s41586-021-03613-0
intvolume: '       594'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1038/s41586-021-03613-0
month: '06'
oa: 1
oa_version: Published Version
page: 454-458
pmid: 1
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Gating and modulation of a hetero-octameric AMPA glutamate receptor
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 594
year: '2021'
...