Danyang Zhang / Josip Ivica / James M Krieger / Hinze Ho / Keitaro Yamashita / Imogen Stockwell / Rozbeh Baradaran / Ondrej Cais / Ingo H Greger /
PubMed Abstract
AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca-impermeable, or GluA2-lacking and Ca-permeable. ...AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca-impermeable, or GluA2-lacking and Ca-permeable. Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies, 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.
EMDB-16381, PDB-8c1r: Resting state homomeric GluA2 F231A mutant AMPA receptor in complex with TARP gamma-2 Method: EM (single particle) / Resolution: 3.2 Å
EMDB-16382, PDB-8c1s: Transmembrane domain of resting state homomeric GluA2 F231A mutant AMPA receptor in complex with TARP gamma 2 Method: EM (single particle) / Resolution: 3.0 Å
EMDB-16390, PDB-8c2h: Transmembrane domain of active state homomeric GluA1 AMPA receptor in tandem with TARP gamma 3 Method: EM (single particle) / Resolution: 2.64 Å
EMDB-16391, PDB-8c2i: Transmembrane domain of resting state homomeric GluA1 AMPA receptor in complex with TARP gamma 3 Method: EM (single particle) / Resolution: 2.7 Å
EMDB-17392, PDB-8p3q: Homomeric GluA2 flip R/G-unedited Q/R-edited F231A mutant in tandem with TARP gamma-2, desensitized conformation 3 Method: EM (single particle) / Resolution: 2.95 Å
EMDB-17393, PDB-8p3s: Homomeric GluA2 flip R/G-unedited Q/R-edited F231A mutant in tandem with TARP gamma-2, desensitized conformation 2 Method: EM (single particle) / Resolution: 2.95 Å
EMDB-17398, PDB-8p3x: Homomeric GluA2 flip R/G-edited Q/R-edited F231A mutant in tandem with TARP gamma-2, desensitized conformation 1 Method: EM (single particle) / Resolution: 3.36 Å
EMDB-17399, PDB-8p3y: Homomeric GluA2 flip R/G-edited Q/R-edited F231A mutant in tandem with TARP gamma-2, desensitized conformation 3 Method: EM (single particle) / Resolution: 3.55 Å
EMDB-17400, PDB-8p3z: Homomeric GluA2 flip R/G-edited Q/R-edited F231A mutant in tandem with TARP gamma-2, desensitized conformation 2 Method: EM (single particle) / Resolution: 3.46 Å
EMDB-17692, PDB-8piv: Homomeric GluA2 flip R/G-unedited Q/R-edited F231A mutant in tandem with TARP gamma-2, desensitized conformation 1 Method: EM (single particle) / Resolution: 3.46 Å
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