THE GAMMA-3-SUBUNIT OF THE GABA-A-RECEPTOR CONFERS SENSITIVITY TO BENZODIAZEPINE RECEPTOR LIGANDS

The gamma-3-subunit of the GABA(A)-receptor in rat brain has been identified by molecular cloning. When co-expressed with the alpha-5- and beta-2-subunits in transfected cells a high potency for GABA (K(a) = 4.9 +/- 1.2-mu-M) and a strong cooperativity in gating the channel (H = 1.9 +/- 0.2) was observed. The GABA response was potentiated in the presence of flunitrazepam and reduced by beta-CCM. An analogous bi-directional modulation of the GABA response was observed with diazepam and DMCM as tested with the subunit combinations alpha-1-beta-2-gamma-3 and alpha-3-beta-2-gamma-3 expressed in Xenopus oocytes. Since the benzodiazepine receptor ligands were virtually inactive in the absence of the gamma-3-subunit, as tested with the alpha-3-beta-2- and alpha-5-beta-2-subunit combinations, the gamma-3-subunit is a prerequisite for the benzodiazepine receptor sensitivity of the expressed GABA(A)-receptors. The gamma-3-subunit could functionally replace the gamma-2-subunit with regard to the bi-directional allosteric drug modulation.