000162951 001__ 162951
000162951 005__ 20260515150539.0
000162951 0247_ $$2doi$$a10.1038/s41586-025-09325-z
000162951 0248_ $$2sideral$$a145437
000162951 037__ $$aART-2025-145437
000162951 041__ $$aeng
000162951 100__ $$aPokharna, Aditya
000162951 245__ $$aArchitecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors
000162951 260__ $$c2025
000162951 5060_ $$aAccess copy available to the general public$$fUnrestricted
000162951 5203_ $$aAMPA-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.
000162951 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PRE2020-092922$$9info:eu-repo/grantAgreement/ES/MCINN/AEI/RYC2018-025720-I$$9info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-106284GA-I00
000162951 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000162951 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000162951 700__ $$aStockwell, Imogen
000162951 700__ $$aIvica, Josip
000162951 700__ $$aSingh, Bishal
000162951 700__ $$aSchwab, Johannes
000162951 700__ $$aVega-Gutiérrez, Carlos$$uUniversidad de Zaragoza
000162951 700__ $$0(orcid)0000-0003-2044-4795$$aHerguedas, Beatriz$$uUniversidad de Zaragoza
000162951 700__ $$aCais, Ondrej
000162951 700__ $$aKrieger, James M.
000162951 700__ $$aGreger, Ingo H.
000162951 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000162951 773__ $$g645, 8080 (2025), 535-543$$pNature$$tNature$$x0028-0836
000162951 8564_ $$s6063442$$uhttps://zaguan.unizar.es/record/162951/files/texto_completo.pdf$$yVersión publicada
000162951 8564_ $$s3262641$$uhttps://zaguan.unizar.es/record/162951/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000162951 909CO $$ooai:zaguan.unizar.es:162951$$particulos$$pdriver
000162951 951__ $$a2026-05-15-15:02:11
000162951 980__ $$aARTICLE