ジャーナル: Nature / 年: 2025 タイトル: Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors. 著者: Aditya Pokharna / Imogen Stockwell / Josip Ivica / Bishal Singh / Johannes Schwab / Carlos Vega-Gutiérrez / Beatriz Herguedas / Ondrej Cais / James M Krieger / Ingo H Greger / 要旨: AMPA-type glutamate receptors (AMPARs) mediate the majority of excitatory neurotransmission in the brain. Assembled from combinations of four core subunits, GluA1-4, and ~20 auxiliary subunits, their ...AMPA-type glutamate receptors (AMPARs) mediate the majority of excitatory neurotransmission in the brain. Assembled from combinations of four core subunits, GluA1-4, and ~20 auxiliary subunits, their molecular diversity tunes information transfer and storage in a brain circuit-specific manner. GluA3, a subtype strongly associated with disease, functions as both a fast transmitting Ca-permeable (CP) AMPAR at sensory synapses, and as a Ca-impermeable (CI) receptor at cortical synapses. Here, we present cryo-EM structures of the CP GluA3 homomer, which substantially diverge from other AMPARs. The GluA3 extracellular domain tiers (NTD and LBD) are closely coupled throughout gating states, creating previously unseen interfaces that impact signalling and harbour human disease 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 conformational stability of the LBD tier. Hence, specific design features define communication and biogenesis of GluA3, offering a framework to interrogate this disease-prone glutamate receptor.