ArticleBritish journal of pharmacology2008
Estimating the efficiency of benzodiazepines on GABA(A) receptors comprising gamma1 or gamma2 subunits.
Article in British journal of pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- γ1 GABAThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABAACS medicinal chemistry letters · 2020Article
- New Aspects of VEGF, GABA, and Glutamate Signaling in the Neocortex of Human Temporal Lobe Pharmacoresistant Epilepsy Revealed by RT-qPCR Arrays.Journal of molecular neuroscience : MN · 2020Article
- A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.Scientific reports · 2020Article
- Structure-Guided Computational Methods Predict Multiple Distinct Binding Modes for Pyrazoloquinolinones in GABAFrontiers in neuroscience · 2020Article
- Article
- Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.European journal of pharmacology · 2011Article
- Tolerance to the rate-increasing and not rate-decreasing effects of pregnanolone in rats.Behavioural pharmacology · 2010Article
- Alcohol- and alcohol antagonist-sensitive human GABAA receptors: tracking δ subunit incorporation into functional receptors.Molecular pharmacology · 2010Article
- The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.European journal of pharmacology · 2010Article
- Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant alpha4beta3delta and alpha4beta3 GABA A receptors expressed in HEK cells.Neuropharmacology · 2009Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeHeterologous expression of alpha1, beta2 and gamma2S(gamma1) subunits produces a mixed population of GABA(A) receptors containing alpha1beta2 or alpha1beta2gamma2S(gamma1) subunits. GABA sensitivity (lower in receptors containing gamma1 or gamma2S subunits) and the potentiation of GABA-activated chloride currents (I(GABA)) by benzodiazepines (BZDs) are dependent on gamma2S(gamma1) incorporation. A variable gamma subunit incorporation may affect the estimation of I(GABA) potentiation by BZDs. We propose an approach for estimation of BZD efficiency that accounts for mixed population of alpha1beta2 and alpha1beta2gamma2S(gamma1) receptors. EXPERIMENTAL APPROACH: We investigated the relation between GABA sensitivity (EC50) and BZD modulation by analysing triazolam-, clotiazepam- and midazolam-induced potentiation of I(GABA) in Xenopus oocytes under two-microelectrode voltage clamp. KEY
resultsPlotting EC50 versus BZD-induced shifts of GABA concentration-response curves (DeltaEC50(BZD)) of oocytes injected with different amounts of alpha1, beta2 and gamma2S(gamma1) cRNA (1:1:1-1:1:10) revealed a linear regression between gamma2S(gamma1)-mediated reduction of GABA sensitivity (EC50) and DeltaEC50(BZD). The slope factors of the regression were always higher for oocytes expressing alpha1beta2gamma1 subunit receptors (1.8 +/- 0.1 (triazolam), 1.6 +/- 0.1 (clotiazepam), 2.3 +/- 0.2 (midazolam)) than for oocytes expressing alpha1beta2gamma2S receptors (1.4 +/- 0.1 (triazolam), 1.4 +/- 0.1 (clotiazepam), 1.3 +/- 0.1 (midazolam)). Mutant GABA(A) receptors (alpha1beta2-R207Cgamma2S) with lower GABA sensitivity showed higher drug efficiencies (slope factors=1.1 +/- 0.1 (triazolam), 1.1 +/- 0.1 (clotiazepam), 1.2 +/- 0.1 (midazolam)). CONCLUSIONS AND IMPLICATIONS: Regression analysis enabled the estimation of BZD efficiency when variable mixtures of alpha1beta2 and alpha1beta2gamma2S(gamma1) receptors are expressed and provided new insights into the gamma2S(gamma1) dependency of BZD action.
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