biostudies-literatureZhou CWhitehall Foundation (Whitehall Foundation, Inc.)U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIGMS NIH HHS10989https://www.ebi.ac.uk/biostudies/studies/S-EPMC12690123biostudies-literatureUnknown16(1)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 conformationNature communicationsStructural insights into kainate receptor desensitization.PMC12690123R35 GM1472661R35GM147266-012022-05-080Segura-Covarrubias GTajima NZhou CfalseStructural insights into kainate receptor desensitization.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 conformation2025-01-01T00:00:00Z2025 Dec2026-06-06T03:54:09.159Z2026-05-25T03:12:17.869ZS-EPMC126901234136585910.1038/s41467-025-65920-8