Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors

Pokharna, Aditya ; Stockwell, Imogen ; Ivica, Josip ; Singh, Bishal ; Schwab, Johannes ; Vega-Gutiérrez, Carlos (Universidad de Zaragoza) ; Herguedas, Beatriz (Universidad de Zaragoza) ; Cais, Ondrej ; Krieger, James M. ; Greger, Ingo H.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/s41586-025-09325-z

Año: 2025

Publicado en: Nature 645, 8080 (2025), 535-543
ISSN: 0028-0836

Financiación: info:eu-repo/grantAgreement/ES/AEI/PRE2020-092922
Financiación: info:eu-repo/grantAgreement/ES/MCINN/AEI/RYC2018-025720-I
Financiación: info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-106284GA-I00

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)