KAINATE RECEPTORS EXHIBIT DIFFERENTIAL SENSITIVITIES TO (S)-5-LODOWILLARDIINE

Characterization of the role of kainate receptors in excitatory synapt ic transmission has been hampered by a lack of subtype-selective pharm acological agents. (S)-5-lodowillardiine (IW), an analog of willardiin e )-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione], a heterocyclic am ino acid found in Acacia and Mimosa seeds, was previously shown to be highly potent on native kainate receptors in dorsal root ganglion neur ons. We examined the responses evoked by IW from recombinant homomeric and heteromeric kainate receptors expressed in human embryonic kidney 293 cells. IW potently elicited currents from glutamate receptor 5 (G luR5)-expressing cells, but showed no activity on homomeric GluR6 or G luR7 receptors. Go-expression of these receptor subunits with KA-2 sub units produced receptors that were weakly sensitive to IW. GluR5/KA-2 receptors had a higher EC50 value than homomeric GluR5 and exhibited a much faster recovery from desensitization, Finally, we found that the IW selectivity for GluR5 compared with GluR6 was determined by amino acid 721, which was previously shown to control ha-amino-3-hydroxy-5-m ethyl-4-isoxazole-propionate sensitivity of these kainate receptor sub units. The pharmacological selectivity and commercial availability of IW suggests that this compound may be of use in characterizing the mol ecular constituents of native kainate receptor responses.