Influence of GABA(A) receptor α subunit isoforms on the benzodiazepine binding site

Lüscher, Benjamin P; Baur, Roland; Goeldner, Maurice; Sigel, Erwin (2012). Influence of GABA(A) receptor α subunit isoforms on the benzodiazepine binding site. PLoS ONE, 7(7), e42101. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0042101

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Classical benzodiazepines, such as diazepam, interact with α(x)β(2)γ(2) GABA(A) receptors, x = 1, 2, 3, 5 and modulate their function. Modulation of different receptor isoforms probably results in selective behavioural effects as sedation and anxiolysis. Knowledge of differences in the structure of the binding pocket in different receptor isoforms is of interest for the generation of isoform-specific ligands. We studied here the interaction of the covalently reacting diazepam analogue 3-NCS with α(1)S204Cβ(2)γ(2), α(1)S205Cβ(2)γ(2) and α(1)T206Cβ(2)γ(2) and with receptors containing the homologous mutations in α(2)β(2)γ(2), α(3)β(2)γ(2), α(5)β(1/2)γ(2) and α(6)β(2)γ(2). The interaction was studied using radioactive ligand binding and at the functional level using electrophysiological techniques. Both strategies gave overlapping results. Our data allow conclusions about the relative apposition of α(1)S204Cβ(2)γ(2), α(1)S205Cβ(2)γ(2) and α(1)T206Cβ(2)γ(2) and homologous positions in α(2), α(3), α(5) and α(6) with C-atom adjacent to the keto-group in diazepam. Together with similar data on the C-atom carrying Cl in diazepam, they indicate that the architecture of the binding site for benzodiazepines differs in each GABA(A) receptor isoform α(1)β(2)γ(2), α(2)β(2)γ(2), α(3)β(2)γ(2), α(5)β(1/2)γ(2) and α(6)β(2)γ(2).

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Lüscher, Benjamin; Baur, Roland and Sigel, Erwin

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:37

Last Modified:

20 Dec 2014 21:33

Publisher DOI:

10.1371/journal.pone.0042101

PubMed ID:

22848717

Web of Science ID:

000306950200165

BORIS DOI:

10.7892/boris.15041

URI:

https://boris.unibe.ch/id/eprint/15041 (FactScience: 222195)

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