Structural basis for activation and conformational plasticity of the GluA4 AMPA receptor

AMPA-subtype glutamate receptors (AMPARs) mediate excitatory synaptic transmission. AMPAR ion channels exhibit multiple subconductance states that tune neuronal responses to glutamate. GluA4 is the rarest subunit in the brain but is enriched in interneurons and the cerebellum. Rising evidence points to GluA4 AMPARs in the development of neurological diseases, but the structural mechanisms of GluA4 function remain enigmatic. Here, we show the distinct features of GluA4 that tune AMPAR function. We find that GluA4 AMPARs have a canonical "Y" shaped architecture where local dimer pairs are domain-swapped between the amino terminal domain (NTD) and ligand binding domain (LBD), both of which comprise the extracellular domain. All four LBDs are glutamate bound yet open the GluA4 ion channel by asymmetric hinging in all four channel helices. We observe that the glutamate-saturated LBD has conformational plasticity, which tunes the ion channel gate below. These data provide a framework for understanding channel subconductance, outline the distinct properties of GluA4, expand our understanding of conformational plasticity in AMPARs, and will inform therapeutic design.