IDENTIFICATION OF AMINO-ACID-RESIDUES THAT CONTROL FUNCTIONAL-BEHAVIOR IN GLUR5 AND GLUR6 KAINATE RECEPTORS

GluR5 and GluR6 kainate receptors differ in their responses to a varie ty of agonists, despite their relatively high primary sequence homolog y. We carried out a structure-function study to identify amino acids u nderlying these divergent responses. Patch clamp analysis of chimeric GluR5-GluR6 receptors indicated that several functionally dominant sit es were localized to the C-terminal side of M1. All nonconserved amino acids in the region between M3 and M4 of GluR6 were then individually mutated to their GluR5 counterparts. We found that a single amino aci d (N721 in GluR6) controls both AM PA sensitivity and domoate deactiva tion rates. Additionally, mutation of A689 in GluR6 slowed kainate des ensitization. These functional effects were accompanied by alterations in binding affinities. These results support a critical role for thes e residues in receptor binding and gating activity.