Partial agonists and heteromeric Kainate receptor desensitization

Kainate receptors (KARs) are glutamate-gated ion channels that mediate fast excitatory synaptic transmission in the central nervous system. KARs assemble as homo- or heterotetramers composed of five subunits (GluK1-5), with heteromeric assemblies representing the predominant native population. Although KARs share overall structures and basic functional properties with other ionotropic glutamate receptor subfamilies, they exhibit distinct gating kinetics, particularly with respect to desensitization. While earlier studies have demonstrated how agonist binding drives gate opening and subsequent desensitization, the mechanisms governing partial agonism and desensitization of KARs, especially in heteromeric KARs, remain incompletely understood. Here, we combine electrophysiology and microscale thermophoresis binding assays to elucidate how distinct KAR partial agonists control KAR desensitization and its recovery. While the onset rates of desensitization of homo- and heteromeric receptors activated by high/saturating concentrations of partial agonists are conserved between GluK2 and GluK2/GluK5 receptors, recovery from desensitization in heteromers is significantly slower than in homomers. Together with structural modeling and analysis of the GluK2 and GluK5 ligand binding domains (LBDs) in complex with orthosteric ligands, we show that agonist residence time and the extent of LBD bi-lobe closure across various agonists take precedence over subunit composition in governing KAR desensitization.