Conformational Landscape of an Agonist-Binding Domain of a Full-Length Heteromeric Kainate Receptor Gluk2/K5 Displaying Partial Agonism

Abstract

Kainate receptors are the family of glutamate-gated ion channels (iGluRs) involved in both excitatory and inhibitory synaptic transmission. Based on their affinity for kainate, they are sub-grouped as low affinity (GluK1-3) and high affinity (GluK4-5). Homomeric GluK2 and heteromeric GluK2/K5 are the most abundant subtypes of kainate receptors found in human brain. Structural data available for homomeric GluK2 have shown differential degree of cleft closure upon binding to different agonists. On contrary, the structural understanding of an agonist binding to the cleft of agonist binding domain of heteromeric GluK2/K5 is limited. In particular, we are interested in understanding the conformational changes induced in heteromer GluK2/K5 in presence of agonist AMPA and iodowillardiine. Functional studies have shown that both AMPA and iodowillardiine serve as partial agonist for heteromer GluK2/K5 and elicit no response in homomeric GluK2. Herein, we present to you our structural investigation for understanding the conformational changes induced in a full-length heteromer GluK2/K5 in presence of its endogenous ligand glutamate and its partial agonist AMPA and iodowillardiine.