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Journal of Neuroscience, Vol 8, 289-295, Copyright © 1988 by Society for Neuroscience
Allosteric modulation by benzodiazepine receptor ligands of the GABAA receptor channel expressed in Xenopus oocytes
E Sigel and R Baur
Department of Pharmacology, University of Bern, Switzerland.
Chick brain mRNA was isolated and injected into Xenopus oocytes. This led
to the expression in the surface membrane of functional GABA- activated
channels with properties reminiscent of vertebrate GABAA channels. The
GABA-induced current was analyzed quantitatively under voltage-clamp
conditions. Picrotoxin inhibited this current in a concentration-dependent
manner with IC50 = 0.6 microM. The allosteric modulation of GABA currents
by a number of drugs acting at the benzodiazepine binding site was
characterized quantitatively. In the presence of the benzodiazepine
receptor ligands diazepam and clorazepate, GABA responses were enhanced,
and in the presence of the convulsant beta-carboline compound methyl
6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylate (DMCM), they were
depressed. Maximal stimulation of the response elicited by 10 microM GABA
was 160% with diazepam and 90% with clorazepate, and maximal inhibition was
42% with DMCM, 30% with methyl beta-carboline-3-carboxylate (beta-CCM), 15%
with ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo
[1,5a][1,4]benzodiazepine-3-carboxylate (Ro 15-1788), and 12% with ethyl
beta-carboline-3-carboxylate (beta-CCE). Half-maximal stimulation was
observed with 20 nM diazepam and 390 nM clorazepate, respectively, and
half-maximal inhibition with 6 nM DMCM. beta-CCM had a similar effect to
DMCM, whereas beta-CCE and Ro 15-1788 showed only small inhibition at low
concentrations (less than 1 microM). All the tested carboline compounds and
Ro 15-1788 showed a biphasic action and stimulated GABA current at
concentrations higher than 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
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