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

Maldifassi, Maria Constanza; Baur, Roland; Sigel, Erwin (2016). Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. Neuropharmacology, 105, pp. 207-214. Elsevier 10.1016/j.neuropharm.2016.01.003

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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 α1β2γ2 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Maldifassi, Maria Constanza; Baur, Roland and Sigel, Erwin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0028-3908

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

04 Mar 2016 11:16

Last Modified:

04 Mar 2016 11:16

Publisher DOI:

10.1016/j.neuropharm.2016.01.003

PubMed ID:

26767954

Uncontrolled Keywords:

Anesthetics; Barbiturates; Chloride channels; Electrophysiology; GABA(A) receptors; Xenopus oocyte

BORIS DOI:

10.7892/boris.76360

URI:

https://boris.unibe.ch/id/eprint/76360

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