Auxiliary subunits keep AMPA receptors compact during activation and desensitization

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Abstract

Signal transduction at vertebrate excitatory synapses involves the rapid activation of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors, glutamate-gated ion channels whose four subunits assemble as a dimer-of-dimers. Technical advances in cryo-electron microscopy brought a slew of full-length structures of AMPA receptors, on their own and in combination with auxiliary subunits. These structures indicate that dimers might undergo substantial lateral motions during gating, opening up the extracellular layer along the central 2-fold symmetry axis. We used bifunctional methanethiosulfonate cross-linkers to calibrate the conformations found in functional AMPA receptors in the presence and absence of the auxiliary subunit Stargazin. Our data indicate that extracellular layer of AMPA receptors can get trapped in stable, opened-up conformations, especially upon long exposures to glutamate. In contrast, Stargazin limits this conformational flexibility. Thus, under synaptic conditions, where brief glutamate exposures and the presence of auxiliary proteins dominate, extracellular domains of AMPA receptors likely stay compact during gating.

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All data generated or analysed during this study are included in the manuscript. Source data files have been provided for Figure 2, 5 and 6.

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Jelena Baranovic

Institute of Biology, Cellular Biophysics, Humboldt Universität zu Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Andrew J R Plested

Institute of Biology, Cellular Biophysics, Humboldt Universität zu Berlin, Berlin, Germany

For correspondence
plested@fmp-berlin.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6062-0832

Funding

H2020 European Research Council (Gluactive (647895))

Andrew J R Plested

Deutsche Forschungsgemeinschaft (NeuroCure EXC-257)

Andrew J R Plested

Deutsche Forschungsgemeinschaft (Heisenberg Professorship)

Andrew J R Plested

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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