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Nature. 2017 Sep 7;549(7670):60-65. doi: 10.1038/nature23479. Epub 2017 Jul 24.

Channel opening and gating mechanism in AMPA-subtype glutamate receptors.

Author information

1
Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, New York 10032, USA.
2
Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, 650 West 168th Street, New York, New York 10032, USA.
3
Howard Hughes Medical Institute, 650 West 168th Street, New York, New York 10032, USA.
4
Department of Biological Sciences, Columbia University, 650 West 168th Street, New York, New York 10032, USA.

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.

PMID:
28737760
PMCID:
PMC5743206
DOI:
10.1038/nature23479
[Indexed for MEDLINE]
Free PMC Article

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