The ?-aminobutyric acid type A (GABAA) receptor is a member of the Cys-loop family of transmitter-gated ion channels. The receptors respond to synaptically-released or ambient transmitter with a conformational change, resulting in the opening of the gate that allows ion movement through the channel. Potentiation of GABAA receptor activity underlies the anesthetic effects of many intravenous anesthetics, such as etomidate and propofol. Although not in active clinical use, neuroactive steroids are among the most potent and efficacious potentiators of the GABAA receptor. Propofol, etomidate and neuroactive steroids also directly activate the GABAA receptor, although the concentrations for direct activation are typically higher than those that cause potentiation. Our preliminary data demonstrate that some neuroactive steroids strongly potentiate gating by propofol or etomidate. Combination of a low concentration of GABA with a low concentration of steroid results in a remarkable, supra-additive, increase in the extent of potentiation. In tadpole and mouse behavioral assays, the presence of a low, subthreshold concentration of a potentiating steroid results in a leftward shift in the dose-response relationship for loss of righting whereas in a cel line the presence of a steroid does not affect etomidate-elicited suppression of cortisol release. The overall goal of the present work is to determine the mechanism of interactions of steroid analogues and intravenous anesthetics on GABAA receptors, and to explore the clinical significance of the findings. We will: i) examine the synergistic effects of steroids with allosterc activators on recombinant synaptic and extrasynaptic GABA expressed in heterologous expression systems;ii) examine the behavioral consequences of synergistic effects of steroids and intravenous anesthetics in tadpole and mouse behavioral assays;and iii) probe whether reduced doses of anesthetics required to produce sedation in the presence of steroids lead to reduced off-target effects. The completion of these aims will increase our understanding of how the GABAA receptor functions in health and disease, and lay a foundation for future development of novel therapeutic approaches.

Public Health Relevance

Potentiation of ?-aminobutyric type A (GABAA) receptors underlies the anesthetic effects of intravenous anesthetics such as etomidate, propofol and barbiturates. This project examines the effect of steroids and steroid analogues on the dosage requirements for intravenous anesthetics to potentiate GABAA receptors and to produce sedation without affecting adverse side effects in animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM108580-01A1
Application #
8758980
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$305,000
Indirect Cost
$105,000
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Eaton, Megan M; Bracamontes, John; Shu, Hong-Jin et al. (2014) ?-aminobutyric acid type A ?4, ?2, and ? subunits assemble to produce more than one functionally distinct receptor type. Mol Pharmacol 86:647-56