Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2014 Dec 01;17123:5446-57. doi: 10.1111/bph.12861.
Show Gene links
Show Anatomy links
The neurosteroid 5β-pregnan-3α-ol-20-one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABAA receptors.
Li P
,
Bracamontes JR
,
Manion BD
,
Mennerick S
,
Steinbach JH
,
Evers AS
,
Akk G
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: Neurosteroids potentiate responses of the GABAA receptor to the endogenous agonist GABA. Here, we examined the ability of neurosteroids to potentiate responses to the allosteric activators etomidate, pentobarbital and propofol.
EXPERIMENTAL APPROACH: Electrophysiological assays were conducted on rat α1β2γ2L GABAA receptors expressed in HEK 293 cells. The sedative activity of etomidate was studied in Xenopus tadpoles and mice. Effects of neurosteroids on etomidate-elicited inhibition of cortisol synthesis were determined in human adrenocortical cells.
KEY RESULTS: The neurosteroid 5β-pregnan-3α-ol-20-one (3α5βP) potentiated activation of GABAA receptors by GABA and allosteric activators. Co-application of 1 μM 3α5βP induced a leftward shift (almost 100-fold) of the whole-cell macroscopic concentration-response relationship for gating by etomidate. Co-application of 100 nM 3α5βP reduced the EC50 for potentiation by etomidate of currents elicited by 0.5 μM GABA by about three-fold. In vivo, 3α5βP (1mg kg(-1) ) reduced the dose of etomidate required to produce loss of righting in mice (ED50 ) by almost 10-fold. In tadpoles, the presence of 50 or 100 nM 3α5βP shifted the EC50 for loss of righting about three- or ten-fold respectively. Exposure to 3α5βP did not influence inhibition of cortisol synthesis by etomidate.
CONCLUSIONS AND IMPLICATIONS: Potentiating neurosteroids act similarly on orthosterically and allosterically activated GABAA receptors. Co-application of neurosteroids with etomidate can significantly reduce dosage requirements for the anaesthetic, and is a potentially beneficial combination to reduce undesired side effects.
Akk,
Mechanisms of neurosteroid interactions with GABA(A) receptors.
2007, Pubmed
Akk,
Mechanisms of neurosteroid interactions with GABA(A) receptors.
2007,
Pubmed
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed
Alexander,
The Concise Guide to PHARMACOLOGY 2013/14: enzymes.
2013,
Pubmed
Alexander,
The Concise Guide to PHARMACOLOGY 2013/14: ligand-gated ion channels.
2013,
Pubmed
Ayub,
Inhibition of human adrenal steroidogenic enzymes in vitro by imidazole drugs including ketoconazole.
1989,
Pubmed
Bäckström,
Pathogenesis in menstrual cycle-linked CNS disorders.
2003,
Pubmed
Belelli,
The in vitro and in vivo enantioselectivity of etomidate implicates the GABAA receptor in general anaesthesia.
2003,
Pubmed
,
Xenbase
Belelli,
The contraceptive agent Provera enhances GABA(A) receptor-mediated inhibitory neurotransmission in the rat hippocampus: evidence for endogenous neurosteroids?
2003,
Pubmed
Chiara,
Specificity of intersubunit general anesthetic-binding sites in the transmembrane domain of the human α1β3γ2 γ-aminobutyric acid type A (GABAA) receptor.
2013,
Pubmed
Coates,
Thiopental is a competitive inhibitor at the human alpha7 nicotinic acetylcholine receptor.
2001,
Pubmed
,
Xenbase
Cotten,
Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression.
2009,
Pubmed
,
Xenbase
Cotten,
Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.
2010,
Pubmed
,
Xenbase
Covey,
Enantioselectivity of pregnanolone-induced gamma-aminobutyric acid(A) receptor modulation and anesthesia.
2000,
Pubmed
Criado,
Induction of anaesthesia with etomidate: haemodynamic study of 36 patients.
1980,
Pubmed
Datta,
Plasma and cerebrospinal fluid progesterone concentrations in pregnant and nonpregnant women.
1986,
Pubmed
de Jong,
Etomidate suppresses adrenocortical function by inhibition of 11 beta-hydroxylation.
1984,
Pubmed
DeLorey,
Barbiturate-benzodiazepine interactions at the gamma-aminobutyric acidA receptor in rat cerebral cortical synaptoneurosomes.
1993,
Pubmed
Dörr,
Etomidate: a selective adrenocortical 11 beta-hydroxylase inhibitor.
1984,
Pubmed
Downie,
Effects of thiopental and its optical isomers on nicotinic acetylcholine receptors.
2000,
Pubmed
,
Xenbase
Eckstein,
Analysis of glutamine, glutamate, pyroglutamate, and GABA in cerebrospinal fluid using ion pairing HPLC with positive electrospray LC/MS/MS.
2008,
Pubmed
Franks,
Molecular targets underlying general anaesthesia.
2006,
Pubmed
Franks,
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.
2008,
Pubmed
Halsey,
Pressure reversal of alphaxalone/alphadolone and methohexitone in tadpoles: evidence for different molecular sites for general anaesthesia.
1986,
Pubmed
Hebron,
Pharmacokinetics of etomidate associated with prolonged i.v. infusion.
1983,
Pubmed
Hendrickx,
Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility.
2008,
Pubmed
Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed
Hosie,
Neurosteroid binding sites on GABA(A) receptors.
2007,
Pubmed
Hunter,
In patients with severe sepsis, does a single dose of etomidate to facilitate intubation increase mortality?
2013,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Li,
Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog.
2006,
Pubmed
Li,
The benzodiazepine diazepam potentiates responses of α1β2γ2L γ-aminobutyric acid type A receptors activated by either γ-aminobutyric acid or allosteric agonists.
2013,
Pubmed
McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed
Miller,
Binding, activation and modulation of Cys-loop receptors.
2010,
Pubmed
Morrow,
The role of neuroactive steroids in ethanol/stress interactions: proceedings of symposium VII at the Volterra conference on alcohol and stress, May 2008.
2009,
Pubmed
Palahniuk,
Pregnancy decreases the requirement for inhaled anesthetic agents.
1974,
Pubmed
Pawson,
The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands.
2014,
Pubmed
Peters,
Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids.
1988,
Pubmed
Ray,
Etomidate for critically ill patients. Pro: yes we can use it.
2012,
Pubmed
Reynolds,
Propofol and flurazepam act synergistically to potentiate GABAA receptor activation in human recombinant receptors.
1996,
Pubmed
,
Xenbase
Reynolds,
Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms.
2003,
Pubmed
Richards,
Additive and non-additive effects of mixtures of short-acting intravenous anaesthetic agents and their significance for theories of anaesthesia.
1981,
Pubmed
Rudolph,
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
1999,
Pubmed
Schumacher,
Steroid hormones and neurosteroids in normal and pathological aging of the nervous system.
2003,
Pubmed
Sebel,
Additive effects of sevoflurane and propofol on gamma-aminobutyric acid receptor function.
2006,
Pubmed
Smith,
Pre-menstrual steroids.
2001,
Pubmed
Solt,
Correlating the clinical actions and molecular mechanisms of general anesthetics.
2007,
Pubmed
Sonner,
Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane.
2007,
Pubmed
Stastna,
Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of δ(16)-alphaxalone and identification of a δ(17(20)) analogue with potent anesthetic activity.
2011,
Pubmed
,
Xenbase
Stewart,
Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation.
2008,
Pubmed
,
Xenbase
Ueno,
Endogenous subunits can cause ambiguities in the pharmacology of exogenous gamma-aminobutyric acidA receptors expressed in human embryonic kidney 293 cells.
1996,
Pubmed
Wagner,
Inhibition of adrenal steroidogenesis by the anesthetic etomidate.
1984,
Pubmed
Weill-Engerer,
Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients.
2002,
Pubmed
Wilder-Smith,
Midazolam premedication reduces propofol dose requirements for multiple anesthetic endpoints.
2001,
Pubmed
Yip,
A propofol binding site on mammalian GABAA receptors identified by photolabeling.
2013,
Pubmed
