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 combi nations. On native rat and cloned human GABA(A) receptors, the anticon vulsant compound loreclezole strongly potentiated GABA-mediated chlori de currents. Using different combinations of human GABA(A) receptor su bunits expressed in Xenopus oocytes and transfected 293 cells, lorecle zole was highly selective for receptors containing the beta 2 or beta 3 subunit over those containing the beta 1 subunit. Loreclezole was de monstrated to act at a site distinct from the benzodiazepine, barbitur ate, and steroid sites with a unique subunit dependence. These results describe a previously unidentified modulatory site on the GABA(A) rec eptor beta subunit that allows pharmacological discrimination of diffe rent GABA(A) receptor subpopulations in the brain and provides a new t arget for putative anticonvulsant/anxiolytic drugs.