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bioRxiv · 10.1101/595009

Homomeric Q/R edited AMPA receptors conduct when desensitized

Coombs, I. D.·Soto, D.·McGee, T. P.·Gold, M. G.·Farrant, M.·Cull-Candy, S. G.
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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 ({gamma}-2, {gamma}-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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Coombs, I. D., Soto, D., McGee, T. P., Gold, M. G., Farrant, M., Cull-Candy, S. G.. 2019-04-01. Homomeric Q/R edited AMPA receptors conduct when desensitized. https://doi.org/10.1101/595009

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