Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. (June 2016)

• Record Type: Journal Article
• Authors: Maldifassi, Maria C.; Baur, Roland; Sigel, Erwin
• Is Part Of: Neuropharmacology. Volume 105(2016)
• Page Start: 207
• Page End: 214
• Publication Date: 2016-06
• Subjects: GABAA receptors -- Chloride channels -- Electrophysiology -- Xenopus oocyte -- Anesthetics -- Barbiturates; GABA gamma-aminobutyric acid -- GABAA receptor gamma-aminobutyric acid type A receptor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.01.003
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs. Among the many modulatory compounds are also the intravenous anesthetics propofol and etomidate, and barbiturates. The mechanism of receptor modulation by these compounds is of mayor relevance. The site of action of these compounds has been located to subunit interfaces in the intra-membrane region of the receptor. In α1 β2 γ2 GABAA receptors there are five such interfaces, two β+/α− and one each of α+/β−, α+/γ− and γ+/β− subunit interfaces. We have used reporter mutations located in the second trans-membrane region in different subunits to probe the effects of changes at these subunit interfaces on modulation by propofol, etomidate and pentobarbital. We provide evidence for the fact that each of these compounds either modulates through a different set of subunit interfaces or through the same set of subunit interfaces to a different degree. As a GABAA receptor pentamer harbors two β+/α− subunit interfaces, we used concatenated receptors to dissect the contribution of individual interfaces and show that only one of these interfaces is important for receptor modulation by etomidate. Highlights: Modulation of α1 β2 γ2 GABAA receptors by intravenous anesthetics was characterized. Propofol etomidate and pentobarbital each act at several subunit interfaces. The set of subunit interfaces was characterized for each of these substances. The two β+/α-subunit interfaces differ in their properties.