SELECTIVE BLOCK OF RECOMBINANT GLUR6 RECEPTORS BY NS-102, A NOVEL NON-NMDA RECEPTOR ANTAGONIST

The diversity of neuronal glutamate receptors continues to increase wi th the discovery of multiple subunits and subunit families. The signif icance of this potential receptor heterogeneity is unknown because pha rmacological tools that could clearly distinguish between different st ructural isoforms have not yet been identified. A novel glutamate rece ptor antagonist, 6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime (N S-102), has been shown previously to selectively block the low affinit y [H-3]kainate binding site in rat brain. We have examined the effect of NS-102 on receptors expressed in fibroblasts from either glur6 subu nits or a combination of glurB and glurD (glurB/D receptors). NS-102 ( 3 mu M) reduced currents mediated by glur6 receptors and had very litt le effect on currents mediated by glurB/D receptors. The binding of [H -3]kainate to glur6 receptors showed properties similar to those of th e brain low affinity [H-3]kainate binding site, and NS-102 inhibited s pecific binding to glur6 receptors with a potency nearly identical to those sites in brain membranes. Our findings suggest that NS-102 will be useful in identifying the functional role of native receptors conta ining a glur6 subunit.