Control of AMPA receptor activity by the extracellular loops of auxiliary proteins

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Abstract

At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of γ2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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Irene Riva

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

Competing interests
The authors declare that no competing interests exist.
Clarissa Eibl

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

Competing interests
The authors declare that no competing interests exist.
Rudolf Volkmer

Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Anna L Carbone

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

For correspondence
carbone@fmp-berlin.de

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

Deutsche Forschungsgemeinschaft (Fellowship and studentship Cluster of Excellence NeuroCure EXC-257)

Anna L Carbone

Austrian Science Fund (Erwin-Schrödinger Postdoctoral Fellowship J3682-B21)

Clarissa Eibl

Deutsche Forschungsgemeinschaft (Research Group Dynion FOR 2518)

Andrew J R Plested

Deutsche Forschungsgemeinschaft (Heisenberg Professor)

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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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.