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Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition

Author

Listed:
  • Jie Yu

    (Oregon Health & Science University)

  • Prashant Rao

    (Oregon Health & Science University)

  • Sarah Clark

    (Oregon Health & Science University)

  • Jaba Mitra

    (University of Illinois at Urbana-Champaign
    Johns Hopkins University)

  • Taekjip Ha

    (Johns Hopkins University
    Johns Hopkins University
    Johns Hopkins University
    Howard Hughes Medical Institute)

  • Eric Gouaux

    (Oregon Health & Science University
    Howard Hughes Medical Institute)

Abstract

AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus1. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes2. Thus far, extensive studies of recombinant AMPA receptor–auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor–auxiliary subunit complexes. The GluA1–GluA2, GluA1–GluA2–GluA3 and GluA2–GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2–SynDIG4 non-stochastically positioned at the B′/D′ and A′/C′ positions, respectively. We further demonstrate how the receptor–TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.

Suggested Citation

  • Jie Yu & Prashant Rao & Sarah Clark & Jaba Mitra & Taekjip Ha & Eric Gouaux, 2021. "Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition," Nature, Nature, vol. 594(7863), pages 448-453, June.
  • Handle: RePEc:nat:nature:v:594:y:2021:i:7863:d:10.1038_s41586-021-03540-0
    DOI: 10.1038/s41586-021-03540-0
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    Cited by:

    1. Amanda M. Perozzo & Jochen Schwenk & Aichurok Kamalova & Terunaga Nakagawa & Bernd Fakler & Derek Bowie, 2023. "GSG1L-containing AMPA receptor complexes are defined by their spatiotemporal expression, native interactome and allosteric sites," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Andrew Muenks & Samantha Zepeda & Guangfeng Zhou & David Veesler & Frank DiMaio, 2023. "Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Diogo Bessa-Neto & Gerti Beliu & Alexander Kuhlemann & Valeria Pecoraro & Sören Doose & Natacha Retailleau & Nicolas Chevrier & David Perrais & Markus Sauer & Daniel Choquet, 2021. "Bioorthogonal labeling of transmembrane proteins with non-canonical amino acids unveils masked epitopes in live neurons," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. Danyang Zhang & Remigijus Lape & Saher A. Shaikh & Bianka K. Kohegyi & Jake F. Watson & Ondrej Cais & Terunaga Nakagawa & Ingo H. Greger, 2023. "Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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