STRUCTURAL AND FUNCTIONAL-CHARACTERIZATION OF THE GAMMA-1 SUBUNIT OF GABA-A BENZODIAZEPINE RECEPTORS

The GABA(A) receptor γ1 subunit of human, rat and bovine origin was molecularly cloned and compared with the γ2 subunit in structure and function. Both γ subunit variants share 74% sequence similarity and are prominently synthesized in often distict areas of the central nervous system as documented by in situ hybridization. When co-expressed with α and β subunits in Xenopus oocytes and mammalian cells, the γ variants mediate the potentiation of GABA evoked currents by benzodiazepines and help generate high-affinity binding sites for these drugs. However, these sites show disparate pharmacological properties which, for receptors assembled from α1, β1 and γ1 subunits, are characterized by the conspicuous loss in affinity for neutral antagonists (e.g. flumazenil) and negative modulators (e.g. DMCM). These findings reveal a pronounced effect of γ subunit variants on GABA(A)/benzodiazepine receptor pharmacology.