Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor

Danyang Zhang, Josip Ivica, James M. Krieger, Hinze Ho, Keitaro Yamashita, Imogen Stockwell, Rozbeh Baradaran, Ondrej Cais and Ingo H. Greger ()
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Danyang Zhang: Medical Research Council (MRC) Laboratory of Molecular Biology
Josip Ivica: Medical Research Council (MRC) Laboratory of Molecular Biology
James M. Krieger: National Center of Biotechnology, CSIC
Hinze Ho: Medical Research Council (MRC) Laboratory of Molecular Biology
Keitaro Yamashita: Medical Research Council (MRC) Laboratory of Molecular Biology
Imogen Stockwell: Medical Research Council (MRC) Laboratory of Molecular Biology
Rozbeh Baradaran: Medical Research Council (MRC) Laboratory of Molecular Biology
Ondrej Cais: Medical Research Council (MRC) Laboratory of Molecular Biology
Ingo H. Greger: Medical Research Council (MRC) Laboratory of Molecular Biology

Nature, 2023, vol. 621, issue 7980, 877-882

Abstract: Abstract AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca2+-impermeable, or GluA2-lacking and Ca2+-permeable1. Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies2, structural information for GluA2-lacking receptors is currently absent. Here we determine and characterize cryo-electron microscopy structures of the GluA1 homotetramer, fully occupied with TARPγ3 auxiliary subunits (GluA1/γ3). The gating core of both resting and open-state GluA1/γ3 closely resembles GluA2-containing receptors. However, the sequence-diverse N-terminal domains (NTDs) give rise to a highly mobile assembly, enabling domain swapping and subunit re-alignments in the ligand-binding domain tier that are pronounced in desensitized states. These transitions underlie the unique kinetic properties of GluA1. A GluA2 mutant (F231A) increasing NTD dynamics phenocopies this behaviour, and exhibits reduced synaptic responses, reflecting the anchoring function of the AMPAR NTD at the synapse. Together, this work underscores how the subunit-diverse NTDs determine subunit arrangement, gating properties and ultimately synaptic signalling efficiency among AMPAR subtypes.

Date: 2023
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DOI: 10.1038/s41586-023-06528-0

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