Bidirectional effect of beta-carboline agonists at the benzodiazepine-GABAA receptor chloride ionophore complex on GABA-stimulated 36Cl- uptake.
beta-Carboline agonists produced a left shift of the GABA concentration-chloride uptake curve or a reduction in the maximal increase in GABA-stimulated 36Cl- uptake depending on their concentration. The enhancement of the GABA effect occurs only at lower beta-carboline and GABA concentrations and is smaller for the partial agonist ZK 9126 compared to the full agonist ZK 93423. The opposite effect, inhibition of GABA-stimulated chloride conductance, is observed only at higher concentrations of beta-carboline agonists and GABA. The reduction of the GABA maximal response by the partial agonist ZK 91296 is greater than by the full agonist ZK 93423. The transformation of GABA-stimulated 36Cl- uptake data to specific chloride influx (36Cl- uptake per nM of GABA) reveals that the GABA concentration-response curve consists of three parts characterized by differences in the molar effectiveness of GABA relative to the GABA concentration. The molar effectiveness of GABA is a measure of the sensitivity of the GABAA receptor chloride ionophore complex and shows adaptive changes by this complex to increasing concentrations of GABA and/or beta-carboline. We conclude from our data that the change from GABA-sensitive to GABA-insensitive conformation of the GABAA receptor occurs with increasing concentrations of GABA and/or beta-carboline. Both conformations maintain positive heterotropic cooperativity with beta-carboline binding sites, one responsible for positive and the other responsible for negative effects of beta-carboline agonists on chloride uptake.
Malatynska
E
E
Department of Psychiatry, Ohio State University, Columbus 43210-1228.
Giroux
M L
ML
Dilsaver
S C
SC
Schwarzkopf
S B
SB
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007476:Ionophores; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D002243:Carbolines; D007476:Ionophores; D011963:Receptors, GABA-A; C038933:ZK 91296; C042569:ZK 93423