当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.

Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.

Abstract：

:Benzodiazepines (BZ) exert their effects through GABAA receptors, which belong to the superfamily of ligand-gated ion channels. Coexpression of recombinant alpha, beta, and gamma subunits in a cell culture system mimics the BZ binding sites. The alpha variants largely determine the nature of the BZ binding site in such alpha i beta j gamma k heteromultimers (i = 1-6; j = 1-3; k = 1-3). Notably, the alpha 1 and alpha 6 variants confer high and low affinity for BZ agonists to the resulting receptor subtype, respectively. Glycine/glutamate and histidine/arginine positions in the alpha subunits of alpha x beta 2 gamma 2 receptors are involved in BZ I versus BZ II type selectivity. We now identify four amino acids in alpha 6 which together increase the affinity of the mutant alpha x beta 2 gamma 2 receptor for classical BZ receptor agonists above the level seen for any wild-type GABAA/BZ receptor. The most pronounced effect was due to an isoleucine to valine exchange. It simultaneously decreased the affinity for the BZ partial inverse agonist Ro 15-4513 20-fold and increased the affinity for diazepam 4-fold. The four amino acid residues stretch over most part of the N-terminal extracellular domain of the alpha subunit, suggesting that amino acids distant in the primary sequence form the BZ binding pocket.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Wieland HA,Lüddens H

doi

10.1021/jm00052a019

subject

Has Abstract

pub_date

1994-12-23 00:00:00

pages

4576-80

issue

26

eissn

0022-2623

issn

1520-4804

journal_volume

37

pub_type

杂志文章

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