Kainate receptors (KARs) belong to the ionotropic glutamate receptor (iGluR) family and play critical roles in mediating excitatory neurotransmission and regulating neurotransmitter release in the brain. KARs can assemble as either homomers or heteromers, with postsynaptic KARs in the CNS predominantly existing as heterotetramers. Receptor desensitization is a key determinant of synaptic transmission strength. Despite their overall structural similarity to AMPA receptors, KARs adopt a desensitized conformation that is strikingly distinct from that of most other iGluRs. Yet, a fundamental question remains unresolved: why do KARs require large conformational changes upon desensitization, and how do homomeric and heteromeric KARs differ functionally and structurally? By combining cryo-electron microscopy and electrophysiology, we demonstrate that lateral rotational movements of the KAR ligand-binding domains are critical for complete channel closure and stabilization of the fully desensitized receptor. Moreover, we show that heteromeric receptors exhibit greater stability, which may represent a defining property of native KARs. Overall, this study elucidates the unique mechanisms and conformational dynamics of KARs. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
N. Tajima (Fri,) studied this question.