GABA(A) Receptor Subtypes : structure, function, distribution and pharmacology

• Unité de recherche: PCRD EU
• Numéro de projet: 96.0010
• Titre du projet anglais: GABA(A) Receptor Subtypes : structure, function, distribution and pharmacology

Mots-clé (Anglais)

GABAA receptor; ligand gated ion channel; benzodiazepines; expression

Autre Numéro de projet (Anglais)

EU project number: BIO4CT960585

Programme de recherche (Anglais)

EU-programme: 4. Frame Research Programme - 4.1 Biotechnology

Description succincte (Anglais)

See abstract

Partenaires et organisations internationales (Anglais)

Universitätsklinik für Psychiatrie, Wien (A), MRC, University of Oxford (GB), CNRS, Gif-sur-Yvette (F)

Résumé des résultats (Abstract) (Anglais)

The GABAA receptor channel is a chloride ion channel essential for neuronal inhibition. It represents the target of many important drugs, among them the benzodiazepines, that have sedative/hypnotic, anxiolytic, muscle relaxant and anticonvulsive properties. The receptor is presumed to be a pentameric protein and molecular biological approaches have identified 18 receptor subunits. Different subunit isoforms confer to the receptor different functional properties and these receptors represent targets for more specifically acting drugs.
New putative ligands of the GABAA receptor based on the competitive GABA antagonist bicuculline and butyrolactone derivatives were synthesized in the collaborating French laboratory and analyzed in our laboratory for activity in modulating receptor function. Structure-function analysis was used to improve the activity of the compounds. The most active ones have been characterized in more detail. Most compounds allosterically stimulate currents elicited by GABA via the benzodiazepine binding site. However introduction of a sulfonamide group seemed to cause action at another, until now undescribed site. These two families of novel ligands have now been patented.
In an attempt to functionally demonstrate the ability of two different a subunit isoforms to coassemble into the same receptor pentamer we expressed the subunit combinations a1b2g2, a6b2g2 and a1a6b2g2 of the GABAA receptor in Xenopus oocytes. Our functional analysis of the respective receptors indicates unambiguously the formation of functional GABAA receptors containing two different a subunits. We provide furthermore evidence for the fact that the formation of the different receptor types depends on the relative abundance of cRNA coding for the different receptor subunits.
In a1, b2 and g2 subunits of the GABAA receptor, a conserved lysine residue occupies the position in the middle of the predicted extracellular loop between the transmembrane M2 and M3 regions. In all three subunits this residue was mutated to alanine. GABA concentration response curves indicated that the apparent affinity of the a1, a1 and b2 subunits mutant receptors for the opening of the channel by GABA was decreased.
Results should contribute to the molecular understanding of events involved in neuronal inhibition and at the same time allow development of drugs affecting it that have novel properties.

Références bases de données (Anglais)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 96.0010