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Publication Detail
Homomeric Q/R edited AMPA receptors conduct when desensitized
  • Publication Type:
    Journal article
  • Authors:
    Coombs I, Soto D, McGee T, Gold M, Farrant M, Cull-Candy S
  • Publisher:
    BioRxiv
  • Publication date:
    01/04/2019
  • Place of publication:
    Cold Spring Harbor, NY, USA
  • Status:
    Published
  • Language:
    English
  • Notes:
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Abstract
Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors, which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we report the surprising finding that homomeric Q/R edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (γ-2, γ-8 or GSG1L), generates large steady-state currents and anomalous current-variance relationships. Using fluctuation analysis, single-channel recording, and kinetic modeling we demonstrate that the steady-state current is mediated predominantly by ‘conducting desensitized’ receptors. When combined with crystallography this unique functional readout of a hith-erto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes within the plasma membrane.
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Neuro, Physiology & Pharmacology
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Neuro, Physiology & Pharmacology
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Neuro, Physiology & Pharmacology
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