9OVT

Heteromeric GluA1/A2 in the inactive state, composite map of LBD-TMD

Summary for 9OVT

• Entry DOI: 10.2210/pdb9ovt/pdb
• EMDB information: 70912
• Descriptor: Glutamate receptor 1, Glutamate receptor 2, {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid, ... (5 entities in total)
• Functional Keywords: glua1a2 heterotetramer zk iglur, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 4
• Total formula weight: 193576.20

Authors

Yen, L.Y.,Sobolevsky, A.I.,Newton, T.P.,Gangwar, S.P. (deposition date: 2025-05-31, release date: 2026-04-08)

Primary citation

Yen, L.Y.,Newton, T.P.,Yelshanskaya, M.V.,Aktolun, M.,Gangwar, S.P.,Clausen, R.P.,Kurnikova, M.G.,Sobolevsky, A.I.
Auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric GluA1/A2 AMPA receptor core.
Nat Commun, 2026

PubMed Abstract: AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate the fast component of excitatory neurotransmission. They govern synaptic plasticity that underlies learning and memory, while their dysregulation is implicated in numerous neurological disorders. The functional diversity of AMPARs arises from variations in their subunit composition and also their association with auxiliary subunits. While multiple structures of homomeric AMPARs have been reported, structural information for the heteromeric core - particularly in the absence of auxiliary subunits, which would serve as a functional and structural baseline - has been limited. Here, we report cryo-electron microscopy structures of GluA1/A2, the most abundant AMPAR di-heteromer in the brain, in the closed, open, and desensitized states. Using molecular dynamics (MD) simulations and cross-correlating structural and functional information, we find that auxiliary subunits increase the diameter of channel pore, which corresponds to larger conductance. Likewise, we find that recovery from desensitization slows with greater disruption of two-fold rotational symmetry of the ligand-binding domain dimer in the desensitized state. Both receptor activation and desensitization vary with the type and number of associated auxiliary proteins. These structures offer a foundation for uncovering how auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric AMPARs.

PubMed: 41904128
DOI: 10.1038/s41467-026-71063-1

Experimental method

ELECTRON MICROSCOPY (3.43 Å)