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| Title | Gating and noelin clustering of native Ca-permeable AMPA receptors. |
|---|---|
| Journal, issue, pages | Nature, Year 2025 |
| Publish date | Jun 23, 2025 |
 Authors | Chengli Fang / Cathy J Spangler / Jumi Park / Natalie Sheldon / Laurence O Trussell / Eric Gouaux /  |
| PubMed Abstract | AMPA-type ionotropic glutamate receptors (AMPARs) are integral to fast excitatory synaptic transmission and play vital roles in synaptic plasticity, motor coordination, learning, and memory. While ...AMPA-type ionotropic glutamate receptors (AMPARs) are integral to fast excitatory synaptic transmission and play vital roles in synaptic plasticity, motor coordination, learning, and memory. While extensive structural studies have been conducted on recombinant AMPARs and native calcium impermeable (CI)-AMPARs alongside their auxiliary proteins, the molecular architecture of native calcium permeable (CP)-AMPARs has remained undefined. To elucidate the subunit composition, physiological architecture, and gating mechanisms of CP-AMPARs, here we present the first visualization of these receptors, immunoaffinity purified from rat cerebella, and resolve their structures using cryo-electron microscopy (cryo-EM). Our results indicate that the predominant assembly consists of GluA1 and GluA4 subunits, with the GluA4 subunit occupying the B and D positions, while auxiliary subunits, including TARPs, are located at the B'/D' positions and CNIHs or TARPs at the A'/C' positions. Furthermore, we resolved the structure of the Noelin 1-GluA1/A4 complex, wherein Noelin 1 (Noe 1) specifically binds to the GluA4 subunit at the B and D positions. Notably, Noe 1 stabilizes the amino-terminal domain (ATD) layer without affecting receptor gating properties. Noe 1 contributes to AMPAR function by forming dimeric-AMPAR assemblies that likely engage in extracellular networks, clustering receptors within synaptic environments and modulating receptor responsiveness to synaptic inputs. |
 External links | Nature / PubMed:40550474 |
| Methods | EM (single particle) |
| Resolution | 3.26 - 9.34 Å |
| Structure data |  EMDB-49711: Cryo-EM map of LBD-TMD combined from all cerebellar CP-AMPAR subtypes with 4 TARPs  EMDB-49712: Cryo-EM map of LBD-TMD combined from all cerebellar CP-AMPAR subtypes with 2 TARPs  EMDB-49713: Cryo-EM map of LBD-TMD combined from all cerebellar CP-AMPAR subtypes with 2 TARPs 2CNIHs  EMDB-49714: Cryo-EM map of Noelin 1 with cerebellar GluA1/A4  EMDB-49715: Cryo-EM map of cerebellar GluA1/A4 with ordered ATD  EMDB-49716: Cryo-EM map of cerebellar GluA1/A4 with disordered ATD  EMDB-49717: Cryo-EM map of LBD-TMD in the active state combined from all cerebellar CP-AMPAR subtypes with 4 auxiliary proteins  EMDB-49718: Cryo-EM map of cerebellar GluA1/A4 LBD-TMD in desensitized state  EMDB-49719: Cryo-EM map of cerebellar GluA1/A4 LBD-TMD in Noelin-AMPAR complex in desensitized state  EMDB-49720: Cryo-EM map of recombinant GluA4 with ordered ATD  EMDB-49721: Cryo-EM map of recombinant GluA4 with disordered ATD  EMDB-49722: Cryo-EM map of recombinant GluA4 with Noelin 1 EMDB-49723: The structure of Noelin 1 with GluA1/A4-ATD EMDB-49724, PDB-9nr7: EMDB-49725, PDB-9nr8: EMDB-49726, PDB-9nr9: EMDB-49727, PDB-9nra: |
| Chemicals |  ChemComp-NAG:  ChemComp-CA:  ChemComp-ZK1: |
| Source |
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 Keywords | MEMBRANE PROTEIN / iGluR / CP-AMPA receptors / Noelin 1 |
rattus norvegicus (Norway rat)
mus musculus (house mouse)