Flunitrazepam has an inverse agonistic effect on recombinant alpha6beta2gamma2-GABAA receptors via a flunitrazepam-binding site.
gamma-Aminobutyric acid type A (GABAA) receptor subtypes containing the alpha6-subunit are generally thought to be insensitive to the action of benzodiazepine agonists. We describe the specific binding of the benzodiazepine agonist flunitrazepam to alpha6beta2gamma2-containing GABAA 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 alpha1beta2gamma2- and alpha6beta2gamma2-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 alpha6beta2gamma2-receptors was opposite to its action on alpha1beta2gamma2-receptors. We conclude that flunitrazepam can act as either an agonist or an inverse agonist, depending on the GABAA receptor configuration.
Hauser
C A
CA
Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstrasse 10, 80804 Munich, Federal Republic of Germany. chhauser@mpipsykl.mpg.de
Wetzel
C H
CH
Berning
B
B
Gerner
F M
FM
Rupprecht
R
R
D000345:Affinity Labels; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D007668:Kidney; D007700:Kinetics; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000345:Affinity Labels; D001386:Azides; D018118:Chloride Channels; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D046911:Macromolecular Substances; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C042957:Ro 15-4513