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Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at gamma-aminobutyric acid type A receptor.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1992 Apr 15; Vol. 89 (8), pp. 3620-4. - Publication Year :
- 1992
-
Abstract
- In central nervous system gamma-aminobutyric acid (GABA) inhibits neuronal activity by acting on GABA type A (GABAA) receptors. These heterooligomeric integral membrane proteins include a GABA-gated Cl- channel and various allosteric modulatory sites where endogenous modulators and anxiolytic drugs act to regulate GABA action. In vivo, various anxiolytic drugs exhibit a wide range of variability in their modulatory efficacy and potency of GABA action. For instance, bretazenil modulatory efficacy is much lower than that of diazepam. Such low efficacy could be due either to a preferential modulation of specific GABAA receptor subtypes or to a low modulatory efficacy at every GABAA receptor subtype. To address these questions we studied drug-induced modifications of GABA-activated Cl- currents in native GABAA receptors of cortical neurons in primary cultures and in recombinant GABAA receptors transiently expressed in transformed human embryonic kidney cells (293) after transfection with cDNAs encoding different molecular forms of alpha, beta, and gamma subunits of GABAA receptors. In cortical neurons the efficacy of bretazenil was lower than that of diazepam, whereas the potency of the two drugs was similar. In cells transfected with gamma 2 subunits and various molecular forms of alpha and beta subunits bretazenil efficacy was always lower than that of diazepam. However, in cells transfected with gamma 1 or gamma 3 subunits and various forms of alpha and beta subunits the efficacy of both diazepam and bretazenil was lower and always of similar magnitude. When bretazenil and diazepam were applied together to GABAA receptors including a gamma 2 subunit, the action of diazepam was curtailed in a manner related to the dose of bretazenil.
- Subjects :
- Allosteric Regulation
Animals
Animals, Newborn
Cell Line
Cells, Cultured
Chloride Channels
Diazepam pharmacology
Dose-Response Relationship, Drug
Humans
Ion Channels physiology
Kidney
Membrane Potentials drug effects
Membrane Proteins drug effects
Membrane Proteins physiology
Neurons drug effects
Rats
Receptors, GABA-A drug effects
Receptors, GABA-A genetics
Transfection
Benzodiazepinones pharmacology
Cerebral Cortex physiology
Neurons physiology
Receptors, GABA-A physiology
gamma-Aminobutyric Acid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 89
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 1373505
- Full Text :
- https://doi.org/10.1073/pnas.89.8.3620