A NOVEL ALLOSTERIC MODULATORY SITE ON THE GABA(A) RECEPTOR-BETA SUBUNIT

Cloning of cDNAs that code for GABA(A) receptor subunits has revealed multiple receptor populations constructed from different subunit combinations. On native rat and cloned human GABA(A) receptors, the anticonvulsant compound loreclezole strongly potentiated GABA-mediated chloride currents. Using different combinations of human GABA(A) receptor subunits expressed in Xenopus oocytes and transfected 293 cells, loreclezole was highly selective for receptors containing the beta 2 or beta 3 subunit over those containing the beta 1 subunit. Loreclezole was demonstrated to act at a site distinct from the benzodiazepine, barbiturate, and steroid sites with a unique subunit dependence. These results describe a previously unidentified modulatory site on the GABA(A) receptor beta subunit that allows pharmacological discrimination of different GABA(A) receptor subpopulations in the brain and provides a new target for putative anticonvulsant/anxiolytic drugs.