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Homomeric GluA2(R) AMPA receptors can conduct when desensitized

Author

Listed:
  • Ian D. Coombs

    (University College London)

  • David Soto

    (University College London
    University of Barcelona)

  • Thomas P. McGee

    (University College London)

  • Matthew G. Gold

    (University College London)

  • Mark Farrant

    (University College London)

  • Stuart G. Cull-Candy

    (University College London)

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 (AMPARs), 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 present evidence 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 fractional steady-state currents and anomalous current-variance relationships. Our results from fluctuation analysis, single-channel recording, and kinetic modeling, suggest that the steady-state current is mediated predominantly by conducting desensitized receptors. When combined with crystallography this unique functional readout of a hitherto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes.

Suggested Citation

  • Ian D. Coombs & David Soto & Thomas P. McGee & Matthew G. Gold & Mark Farrant & Stuart G. Cull-Candy, 2019. "Homomeric GluA2(R) AMPA receptors can conduct when desensitized," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12280-9
    DOI: 10.1038/s41467-019-12280-9
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    Cited by:

    1. 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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