000163058 001__ 163058 000163058 005__ 20251009133841.0 000163058 0247_ $$2doi$$a10.1038/s41594-025-01666-7 000163058 0248_ $$2sideral$$a145491 000163058 037__ $$aART-2025-145491 000163058 041__ $$aeng 000163058 100__ $$aVega-Gutiérrez, Carlos$$uUniversidad de Zaragoza 000163058 245__ $$aGluA4 AMPA receptor gating mechanisms and modulation by auxiliary proteins 000163058 260__ $$c2025 000163058 5203_ $$aAMPA-type glutamate receptors, fundamental ion channels for fast excitatory neurotransmission and synaptic plasticity, contain a GluA tetrameric core surrounded by auxiliary proteins such as transmembrane AMPA receptor regulatory proteins (TARPs) or Cornichons. Their exact composition and stoichiometry govern functional properties, including kinetics, calcium permeability and trafficking. The GluA1–GluA3 subunits predominate in the adult forebrain and are well characterized. However, we lack structural information on full-length GluA4-containing AMPARs, a subtype that has specific roles in brain development and specific cell types in mammals. Here we present the cryo-electron microscopy structures of rat GluA4:TARP-γ2 trapped in active, resting and desensitized states, covering a full gating cycle. Additionally, we describe the structure of GluA4 alone, which displays a classical Y-shaped conformation. In resting conditions, GluA4:TARP-γ2 adopts two conformations, one resembling the desensitized states of other GluA subunits. Moreover, we identify a regulatory site for TARP-γ2 in the ligand-binding domain that modulates gating kinetics. Our findings uncover distinct features of GluA4, highlighting how subunit composition and auxiliary proteins shape receptor structure and dynamics, expanding glutamatergic signaling diversity. 000163058 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PRE2020-092922$$9info:eu-repo/grantAgreement/EC/H2020/871037/EU/Infrastructure for transnational access and discovery in structural biology/iNEXT-Discovery$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 871037-iNEXT-Discovery$$9info:eu-repo/grantAgreement/ES/MCINN/AEI/RYC2018-025720-I$$9info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-106284GA-I00 000163058 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000163058 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000163058 700__ $$aPicañol-Párraga, Javier 000163058 700__ $$aSánchez-Valls, Irene$$uUniversidad de Zaragoza 000163058 700__ $$aRibón-Fuster, Victoria del Pilar$$uUniversidad de Zaragoza 000163058 700__ $$aSoto, David 000163058 700__ $$0(orcid)0000-0003-2044-4795$$aHerguedas, Beatriz$$uUniversidad de Zaragoza 000163058 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000163058 773__ $$pNATURE STRUCTURAL & MOLECULAR BIOLOGY$$tNATURE STRUCTURAL & MOLECULAR BIOLOGY$$x1545-9993 000163058 8564_ $$s20597651$$uhttps://zaguan.unizar.es/record/163058/files/texto_completo.pdf$$yVersión publicada 000163058 8564_ $$s2746311$$uhttps://zaguan.unizar.es/record/163058/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000163058 909CO $$ooai:zaguan.unizar.es:163058$$particulos$$pdriver 000163058 951__ $$a2025-10-09-13:25:56 000163058 980__ $$aARTICLE