The γ3‐subunit of the GABAA‐receptor confers sensitivity to benzodiazepine receptor ligands

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Abstract
The γ3-subunit of the GABAA-receptor in rat brain has been identified by molecular cloning. When co-expressed with the α5- and β2-subunits in transfected cells a high potency for GABA (Ka = 4.9 ± 1.2 μM; 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 reduced by βCCM. An analogous bi-directional modulation of the GABA response was observed with diazepam and DMCM as tested with the subunit combinations α1β2γ3 and α3β2γ3 expressed in Xenopus oocytes. Since the benzodiazepine receptor ligands were virtually inactive in the absence of the γ3-subunit, as tested with the α3β2- and α5β2-subunit combinations, the γ3-subunit is a prerequisite for the benzodiazepine receptor sensitivity of the expressed GABAA-receptors. The γ3-subunit could functionally replace the γ2-subunit with regard to the bi-directional allosteric drug modulation