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Channel opening and gating mechanism in AMPA-subtype glutamate receptors

Author

Listed:
  • Edward C. Twomey

    (Columbia University
    Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University)

  • Maria V. Yelshanskaya

    (Columbia University)

  • Robert A. Grassucci

    (Columbia University
    Howard Hughes Medical Institute)

  • Joachim Frank

    (Columbia University
    Howard Hughes Medical Institute
    Columbia University)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the neurotransmitter glutamate, AMPA receptors are critical for synaptic strength, and dysregulation of AMPA receptor-mediated signalling is linked to numerous neurological diseases. Here we use cryo-electron microscopy to solve the structures of AMPA receptor–auxiliary subunit complexes in the apo, antagonist- and agonist-bound states and determine the iris-like mechanism of ion channel opening. The ion channel selectivity filter is formed by the extended portions of the re-entrant M2 loops, while the helical portions of M2 contribute to extensive hydrophobic interfaces between AMPA receptor subunits in the ion channel. We show how the permeation pathway changes upon channel opening and identify conformational changes throughout the entire AMPA receptor that accompany activation and desensitization. Our findings provide a framework for understanding gating across the family of ionotropic glutamate receptors and the role of AMPA receptors in excitatory neurotransmission.

Suggested Citation

  • Edward C. Twomey & Maria V. Yelshanskaya & Robert A. Grassucci & Joachim Frank & Alexander I. Sobolevsky, 2017. "Channel opening and gating mechanism in AMPA-subtype glutamate receptors," Nature, Nature, vol. 549(7670), pages 60-65, September.
    • Handle: RePEc:nat:nature:v:549:y:2017:i:7670:d:10.1038_nature23479
    DOI: 10.1038/nature23479
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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. Johansen B. Amin & Miaomiao He & Ramesh Prasad & Xiaoling Leng & Huan-Xiang Zhou & Lonnie P. Wollmuth, 2023. "Two gates mediate NMDA receptor activity and are under subunit-specific regulation," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. 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.
    4. Madeleine R. Wilcox & Aparna Nigam & Nathan G. Glasgow & Chamali Narangoda & Matthew B. Phillips & Dhilon S. Patel & Samaneh Mesbahi-Vasey & Andreea L. Turcu & Santiago Vázquez & Maria G. Kurnikova & , 2022. "Inhibition of NMDA receptors through a membrane-to-channel path," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Beatriz Herguedas & Bianka K. Kohegyi & Jan-Niklas Dohrke & Jake F. Watson & Danyang Zhang & Hinze Ho & Saher A. Shaikh & Remigijus Lape & James M. Krieger & Ingo H. Greger, 2022. "Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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