Kainate receptors (KARs) belong to the ionotropic glutamate receptor (iGluR) family and play critical roles in mediating excitatory neurotransmission and regulating neurotransmitter release. Receptor desensitization is a critical factor for regulating the strength of synaptic transmission. Notwithstanding their overall structural similarity to AMPA receptors, KARs exhibit a desensitized conformation that is distinct from that of most other iGluRs. Despite extensive studies on KARs, a fundamental question remains unresolved: why do KARs require large conformational changes upon desensitization? Here we show cryo-electron microscopy structures of GluK2 containing double cysteine mutations, captured in non-active and various desensitized conformations. In the shallow-desensitized conformation, two cysteine crosslinks stabilize the receptors in a conformation resembling the typical desensitized state of non-KAR iGluRs. Our patch-clamp recordings and fluctuation analysis suggest that KARs in the shallow-desensitized state remain ion-permeable. This finding indicates that the lateral rotational movement of the KAR ligand-binding domains is critical for complete channel closure and stabilization of the fully desensitized receptor. Overall, this study elucidates the mechanism and conformational dynamics of KARs during desensitization.
Zhou et al. (Tue,) studied this question.