A closer look at the high affinity benzodiazepine binding site on GABAA receptors

Sigel, Erwin; Lüscher, Benjamin P (2011). A closer look at the high affinity benzodiazepine binding site on GABAA receptors. Current topics in medicinal chemistry, 11(2), pp. 241-6. Hilversum: Bentham Science Publishers 10.2174/156802611794863562

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Ligands of the benzodiazepine binding site of the GABA(A) receptor come in three flavors: positive allosteric modulators, negative allosteric modulators and antagonists all of which can bind with high affinity. The GABA(A) receptor is a pentameric protein which forms a chloride selective ion channel and ligands of the benzodiazepine binding site stabilize three different conformations of this protein. Classical benzodiazepines exert a positive allosteric effect by increasing the apparent affinity of channel opening by the agonist γ-aminobutyric acid (GABA). We concentrate here on the major adult isoform, the α(1)β(2)γ(2) GABA(A) receptor. The classical binding pocket for benzodiazepines is located in a subunit cleft between α(1) and γ(2) subunits in a position homologous to the agonist binding site for GABA that is located between β(2) and α(1) subunits. We review here approaches to this picture. In particular, point mutations were performed in combination with subsequent analysis of the expressed mutant proteins using either electrophysiological techniques or radioactive ligand binding assays. The predictive power of these methods is assessed by comparing the results with the predictions that can be made on the basis of the recently published crystal structure of the acetylcholine binding protein that shows homology to the N-terminal, extracellular domain of the GABA(A) receptor. In addition, we review an approach to the question of how the benzodiazepine ligands are positioned in their binding pocket. We also discuss a newly postulated modulatory site for benzodiazepines at the α(1)/β(2) subunit interface, homologous to the classical benzodiazepine binding pocket.

Item Type:	Journal Article (Further Contribution)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Sigel, Erwin
ISSN:	1568-0266
Publisher:	Bentham Science Publishers
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:23
Last Modified:	05 Dec 2022 14:06
Publisher DOI:	10.2174/156802611794863562
PubMed ID:	21189125
Web of Science ID:	000286222000010
URI:	https://boris.unibe.ch/id/eprint/8167 (FactScience: 213660)