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Volume 271, Number 44, Issue of November 1, 1996 pp. 27902-27911
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular and Pharmacological Characterization of Native Cortical gamma -Aminobutyric AcidA Receptors Containing Both alpha 1 and alpha 3 Subunits

(Received for publication, June 13, 1996, and in revised form, August 2, 1996)

Francisco Araujo Dagger , Suan Tan § , Diego Ruano Dagger , Hans Schoemaker § , Jesus Benavides § and Javier Vitorica Dagger

From the Dagger  Departamento Bioquimica, Bromatologia, y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain and § Central Nervous System Research Department, Synthelabo Recherche, BP 110, 92225 Bagneux Cedex, France

We have investigated the existence, molecular composition, and benzodiazepine binding properties of native cortical alpha 1-alpha 3 gamma -aminobutyric acidA (GABAA) receptors using subunit-specific antibodies.

The co-existence of alpha 1 and alpha 3 subunits in native GABAA receptors was demonstrated by immunoblot analysis of the anti-alpha 1- or anti-alpha 3-immunopurified receptors and by immunoprecipitation experiments of the [3H]zolpidem binding activity. Furthermore, immunodepletion experiments indicated that the alpha 1-alpha 3 GABAA receptors represented 54.7 ± 5.0 and 23.6 ± 3.3% of the alpha 3 and alpha 1 populations, respectively. Therefore, alpha 1 and alpha 3 subunits are associated in the same native GABAA receptor complex, but, on the other hand, these alpha 1-alpha 3 GABAA receptors from the cortex constitute a large proportion of the total alpha 3 population and a relatively minor component of the alpha 1 population.

The pharmacological analysis of the alpha 1- or alpha 3-immunopurified receptors demonstrated the presence of two different benzodiazepine binding sites in each receptor population with high (type I binding sites) and low (type II binding sites) affinities for zolpidem and Cl 218,872. These results indicate the existence of native GABAA receptors possessing both alpha 1 and alpha 3 subunits, with alpha 1 and alpha 3 subunits expressing their characteristic benzodiazepine pharmacology.

The molecular characterization of the anti-alpha 1-anti-alpha 3 double-immunopurified receptors demonstrated the presence of stoichiometric amounts of alpha 1 and alpha 3 subunits, associated with beta 2/3, and gamma 2 subunits. The pharmacological analysis of alpha 1-alpha 3 GABAA receptors demonstrated that, despite the fact that each alpha  subunit retained its benzodiazepine binding properties, the relative proportion between type I and II binding sites or between 51- and 59-61-kDa [3H]Ro15-4513-photolabeled peptides was 70:30. Therefore, the alpha 1 subunit is pharmacologically predominant over the alpha 3 subunit. These results indicate the existence of active and nonactive alpha  subunits in the native alpha 1-alpha 3 GABAA receptors from rat cortex.


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