Bidirectional effect of β-carboline agonists at the benzodiazepine-GABAA receptor chloride ionophore complex on GABA-stimulated 36Cl− uptake
| Autor: | Monique L. Giroux, Steven B. Schwarzkopf, Ewa Malatynska, Steven C. Dilsaver |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Agonist
medicine.medical_specialty medicine.drug_class Allosteric regulation Ionophore In Vitro Techniques Partial agonist Chloride Internal medicine medicine Animals Cerebral Cortex Benzodiazepine Ionophores GABAA receptor Chemistry General Neuroscience Rats Inbred Strains Receptors GABA-A Rats Endocrinology Anti-Anxiety Agents nervous system ZK-93423 Carbolines medicine.drug |
| Zdroj: | Brain Research Bulletin. 28:605-611 |
| ISSN: | 0361-9230 |
| DOI: | 10.1016/0361-9230(92)90110-j |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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