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-Structure paper
Title | Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition. |
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Journal, issue, pages | Nature, Vol. 594, Issue 7863, Page 448-453, Year 2021 |
Publish date | May 12, 2021 |
Authors | Jie Yu / Prashant Rao / Sarah Clark / Jaba Mitra / Taekjip Ha / Eric Gouaux / |
PubMed Abstract | AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and pharmacology of AMPA receptors are ...AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor. |
External links | Nature / PubMed:33981040 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.25 - 7.5 Å |
Structure data | EMDB-23283, PDB-7ldd: EMDB-23284, PDB-7lde: EMDB-23285: native AMPA receptor EMDB-23286: native AMPA receptor EMDB-23287: native AMPA receptor EMDB-23288: native AMPA receptor EMDB-23289: EMDB-23290: EMDB-23292, PDB-7lep: |
Chemicals | ChemComp-ZK1: ChemComp-R16: ChemComp-OCT: ChemComp-HP6: ChemComp-D10: ChemComp-NAG: ChemComp-D12: ChemComp-C14: ChemComp-DD9: ChemComp-XVD: ChemComp-POV: |
Source |
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Keywords | MEMBRANE PROTEIN/IMMUNE SYSTEM / neurotransmitter / two-fold symmetry / hippocampus / ion-channel / MEMBRANE PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / glycosylation / Native hippocampal ion channel |