Research Article

Structure and organization of heteromeric AMPA-type glutamate receptors

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Science  10 Mar 2016:
aad3873
DOI: 10.1126/science.aad3873

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Abstract

AMPA-type glutamate receptors (AMPARs), central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the GluA1-4 subunits. Here we report first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomers. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine crosslinking in full-length receptors and permitted us to determine the structure of an intact GluA2/3 receptor by cryo-EM. Two models in the ligand-free state, at 8.25 Å and 10.3 Å resolution, exhibit a substantial vertical compression and close associations between domain layers, reminiscent of NMDA receptors. Model 1 resembles a resting state, model 2 a desensitized state, providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling.

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