Structural Insights into GluK3-kainate Receptor Desensitization and Recovery

Abstract

GluK3-kainate receptors are atypical members of the iGluR family that reside at both the pre-and postsynapse and play key role in regulation of synaptic transmission. For better understanding of structural changes that underlie receptor recovery from desensitized state, GluK3 receptors were trapped in desensitized and resting/closed states and structures analyzed using single particle cryo-electron microscopy. We show that receptor recovery from desensitization requires major rearrangements of the ligand binding domains (LBD) while the amino terminal (ATD) and transmembrane domains remain virtually unaltered. While, the desensitized GluK3 has domain organization as seen earlier for another kainate receptor-GluK2, antagonist bound GluK3 trapped a partially "recovered" state with only two LBD domains in dimeric arrangement necessary for receptor activation. Using these structures as guide, we show that the N-linked glycans at the interface of GluK3 ATD and LBD likely mediate inter-domain interactions and attune receptor-gating properties. Mutational analysis also identifies putative N-glycan interacting residues. These results provide a molecular framework for understanding gating properties unique to GluK3 and identify role of N-linked glycosylation in their modulation.