Relative positioning of classical benzodiazepines to the γ2-subunit of GABAA receptors.

Middendorp, Simon; Hurni, Evelyn; Schönberger, Matthias; Stein, Marco; Pangerl, Michael; Trauner, Dirk; Sigel, Erwin (2014). Relative positioning of classical benzodiazepines to the γ2-subunit of GABAA receptors. ACS Chemical Biology, 9(8), pp. 1846-1853. American Chemical Society 10.1021/cb500186a

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GABAA receptors are the major inhibitory neurotransmitter receptors in the brain. Benzodiazepine exert their action via a high affinity-binding site at the α/γ subunit interface on some of these receptors. Diazepam has sedative, hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. It acts by potentiating the current evoked by the agonist GABA. Understanding specific interaction of benzodiazepines in the binding pocket of different GABAA receptor isoforms might help to separate these divergent effects. As a first step, we characterized the interaction between diazepam and the major GABAA receptor isoform α1β2γ2. We mutated several amino acid residues on the γ2-subunit assumed to be located near or in the benzodiazepine binding pocket individually to cysteine and studied the interaction with three ligands that are modified with a cysteine-reactive isothiocyanate group (-NCS). When the reactive NCS group is in apposition to the cysteine residue this leads to a covalent reaction. In this way, three amino acid residues, γ2Tyr58, γ2Asn60, and γ2Val190 were located relative to classical benzodiazepines in their binding pocket on GABAA receptors.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Middendorp, Simon, Sigel, Erwin

Subjects:

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

ISSN:

1554-8929

Publisher:

American Chemical Society

Language:

English

Submitter:

Barbara Franziska Järmann-Bangerter

Date Deposited:

13 Mar 2015 09:35

Last Modified:

05 Dec 2022 14:42

Publisher DOI:

10.1021/cb500186a

PubMed ID:

24918742

BORIS DOI:

10.7892/boris.64436

URI:

https://boris.unibe.ch/id/eprint/64436

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