scholarly journals Area-specific regulation of  -aminobutyric acid type A receptor subtypes by thalamic afferents in developing rat neocortex

1997 ◽  
Vol 94 (13) ◽  
pp. 6995-7000 ◽  
Author(s):  
J. Paysan ◽  
A. Kossel ◽  
J. Bolz ◽  
J.-M. Fritschy
Keyword(s):  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Subtypes ◽  
Acid Type ◽  
Rat Neocortex ◽  
Specific Regulation ◽  
Developing Rat

Opposing Actions of Etomidate on Cortical Theta Oscillations Are Mediated by Different γ-Aminobutyric Acid Type A Receptor Subtypes

2005 ◽  
Vol 102 (2) ◽  
pp. 346-352 ◽  
Author(s):  
Berthold Drexler ◽  
Claire L. Roether ◽  
Rachel Jurd ◽  
Uwe Rudolph ◽  
Bernd Antkowiak
Keyword(s):  
Gabaa Receptors ◽  
Type A ◽  
Mutant Mice ◽  
Theta Oscillations ◽  
Aminobutyric Acid ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Action Potential Firing ◽  
Acid Type

Background Cortical networks generate diverse patterns of rhythmic activity. Theta oscillations (4-12 Hz) are commonly observed during spatial learning and working memory tasks. The authors ask how etomidate, acting predominantly via gamma-aminobutyric acid type A (GABAA) receptors containing beta2 or beta3 subunits, affects theta activity in vitro. Methods To characterize the effects of etomidate, the authors recorded action potential firing together with local field potentials in slice cultures prepared from the neocortex of the beta3(N265M) knock-in mutant and wild type mice. Actions of etomidate were studied at 0.2 microm, which is approximately 15% of the concentration causing immobility ( approximately 1.5 microm). Results In preparations derived from wild type and beta3(N265M) mutant mice, episodes of ongoing activity spontaneously occurred at a frequency of approximately 0.1 Hz and persisted for several seconds. Towards the end of these periods, synchronized oscillations in the theta band developed. These oscillations were significantly depressed in slices from beta3(N265M) mutant mice (P < 0.05). In this preparation etomidate acts almost exclusively via beta2 subunit containing GABAA receptors. In contrast, no depression was observed in slices from wild type mice, where etomidate potentiates both beta2- and beta3-containing GABAA receptors. Conclusions At concentrations assumed to cause sedation and amnesia, etomidate depresses theta oscillations via beta2-containing GABAA receptors but enhances these oscillations by acting on beta3 subunit containing receptors. This indicates that the overall effect of the anesthetic reflects a balance between enhancement and inhibition produced by different GABAA receptor subtypes.

scholarly journals Analogues of Etomidate

2014 ◽  
Vol 121 (2) ◽  
pp. 290-301 ◽  
Author(s):  
Ervin Pejo ◽  
Peter Santer ◽  
Spencer Jeffrey ◽  
Hilary Gallin ◽  
S. Shaukat Husain ◽  
...  
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Type A ◽  
Chiral Center ◽  
Aminobutyric Acid ◽  
Adrenocortical Function ◽  
Receptor Subtypes ◽  
Structure Activity ◽  
Acid Type ◽  
Righting Reflex

Abstract Background: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure–activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate’s chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). Methods: The γ-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed α1(L264T)β3γ2L and α1(L264T)β1γ2L γ-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). Results: All four drugs activated both γ-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest γ-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing β3 subunits than β1 subunits; however, dihydrogen etomidate’s subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. Conclusion: The linkage between the structure of etomidate’s chiral center and its pharmacology suggests that altering etomidate’s chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities.

Differentiating the role of γ-aminobutyric acid type A (GABAA) receptor subtypes

2004 ◽  
Vol 32 (3) ◽  
pp. 553-556 ◽  
Author(s):  
K.A. Wafford ◽  
A.J. Macaulay ◽  
R. Fradley ◽  
G.F. O'Meara ◽  
D.S. Reynolds ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Acid Type ◽  
Gabaa Receptor Subtypes ◽  
Subtype Selective

The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (γ-aminobutyric acid type A) receptors. This receptor family comprises various subtypes that have unique regional distributions, but little is known about the role played by each subtype. The majority of the receptors contain a γ2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to α and β subunits. Mutagenesis studies combined with molecular modelling have enabled a greater understanding of receptor structure and dynamics. This can now be extended to in vivo activity through translation to genetically modified mice containing these mutations. Ideally, the mutation should leave normal receptor function intact, and this is the case with mutations affecting the BZ-binding site of the GABAA receptor. We have generated mutations, which affect the BZ site of different α subunits, to enable discrimination of the various behavioural consequences of BZ drug action. This has aided our understanding of the roles played by individual GABAA receptor subtypes in particular behaviours. We have also used this technique to explore the role of different β subunits in conferring the anaesthetic activity of etomidate. This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype.

Sign in / Sign up

Export Citation Format

Share Document