γ-Aminobutyric acid type A (GABA(A)) receptor subtypes containing the α6-subunit are generally thought to be insensitive to the action of benzodiazepine agonists. We describe the specific binding of the benzodiazepine agonist flunitrazepam to α6β2γ2-containing GABA(A) receptors, which has not been observed before and differs from previous reports. With the whole-cell voltage-clamp technique, we observed a functional discrimination between α1β2γ2 and α6β2γ2-receptors. Different benzodiazepines had different effects on GABA-evoked chloride currents. The agonist flunitrazepam had an inverse agonistic effect, whereas the antagonist flumazenil increased GABA-induced chloride currents. The action of flunitrazepam on the channel activity of α6β2γ2-receptors was opposite to its action on α1β2γ2-receptors. We conclude that flunitrazepam can act as either an agonist or an inverse agonist, depending on the GABA(A) receptor configuration.
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