Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors

Aditya Pokharna, Imogen Stockwell, Josip Ivica, Bishal Singh, Johannes Schwab, Carlos Vega-Gutiérrez, Beatriz Herguedas, Ondrej Cais, James M. Krieger and Ingo H. Greger ()
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Aditya Pokharna: Medical Research Council (MRC) Laboratory of Molecular Biology
Imogen Stockwell: Medical Research Council (MRC) Laboratory of Molecular Biology
Josip Ivica: Medical Research Council (MRC) Laboratory of Molecular Biology
Bishal Singh: Medical Research Council (MRC) Laboratory of Molecular Biology
Johannes Schwab: Medical Research Council (MRC) Laboratory of Molecular Biology
Carlos Vega-Gutiérrez: University of Zaragoza
Beatriz Herguedas: University of Zaragoza
Ondrej Cais: Medical Research Council (MRC) Laboratory of Molecular Biology
James M. Krieger: CSIC
Ingo H. Greger: Medical Research Council (MRC) Laboratory of Molecular Biology

Nature, 2025, vol. 645, issue 8080, 535-543

Abstract: Abstract AMPA-type glutamate receptors (AMPARs) mediate the majority of excitatory neurotransmission in the brain1. Assembled from combinations of four core subunits, GluA1–4 and around 20 auxiliary subunits, their molecular diversity tunes information transfer and storage in a brain-circuit-specific manner. GluA3, a subtype strongly associated with disease2, functions as both a fast-transmitting Ca2+-permeable AMPAR at sensory synapses3, and as a Ca2+-impermeable receptor at cortical synapses4,5. Here we present cryo-electron microscopy structures of the Ca2+-permeable GluA3 homomer, which substantially diverges from other AMPARs. The GluA3 extracellular domain tiers (N-terminal domain (NTD) and ligand-binding domain (LBD)) are closely coupled throughout gating states, creating interfaces that impact signalling and contain human disease-associated mutations. Central to this architecture is a stacking interaction between two arginine residues (Arg163) in the NTD dimer interface, trapping a unique NTD dimer conformation that enables close contacts with the LBD. Rupture of the Arg163 stack not only alters the structure and dynamics of the GluA3 extracellular region, but also increases receptor trafficking and the expression of GluA3 heteromers at the synapse. We further show that a mammalian-specific GluA3 trafficking checkpoint determines the conformational stability of the LBD tier. Thus, specific design features define communication and biogenesis of GluA3, offering a framework to examine this disease-associated glutamate receptor.

Date: 2025
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DOI: 10.1038/s41586-025-09325-z

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