Mapping the Ligand Binding Sites of Kainate Receptors: Molecular Determinants of Subunit-Selective Binding of the Antagonist [3H]UBP310

Kainate receptors (KARs) modulate synaptic transmission and plasticity, and their dysfunction has been linked to several disease states such as epilepsy and chronic pain. KARs are tetramers formed from five different subunits. GluK1–3 are low affinity kainate binding subunits, whereas GluK4/5 bind kainate with high affinity. A number of these subunits can be present in any given cell type, and different combinations of subunits confer different properties to KARs. Here we report the characterization of a new GluK1 subunit-selective radiolabeled antagonist (S)-1-(2-amino-2carboxyethyl)-3-(2-carboxythiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione ([ 3 H]UBP310) using human recombinant KARs. [ 3 H]UBP310 binds to GluK1 with low nanomolar affinity (KD