Architecture, Activation, and Conformational Plasticity in the GluA4 AMPA Receptor

Abstract AMPA-subtype glutamate receptors (AMPARs), composed of subunits GluA1-4, mediate fast, excitatory synaptic transmission in the brain. After glutamate binding, 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. Rising evidence points to the role of GluA4 AMPARs in the development of neurological diseases, but the structural mechanisms of GluA4 function have remained enigmatic. Here, from bilayer recordings and cryo-electron microscopy (cryo-EM), we report the unique features of GluA4 AMPARs that tune receptor function. We find that GluA4 AMPARs have a canonical “Y” shaped architecture where local dimer pairs are domain-swapped between the amino terminal domain (ATD) 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 channel helices. We observe that the glutamate-saturated LBD has conformational plasticity, and the different conformations of the LBD tune the ion channel gate below. These data provide a framework for understanding how channel subconductance can occur during conditions of saturating glutamate, outline the unique properties of GluA4, expand our understanding of conformational plasticity in AMPARs, and will inform therapeutic design. Competing Interest Statement R.L.H. is a scientific cofounder and scientific advisory board (SAB) member of Neumora Therapeutics and an SAB member of MAZE Therapeutics. The other authors declare no competing interests.