Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors.

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Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ

Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors.

Mol Pharmacol. 1996 Feb;49(2):253-9.

PubMed ID

8632757 [ View in PubMed

]

Abstract

A cDNA encoding the human gamma-aminobutyric acidA (GABAA) receptor alpha 6 subunit has been cloned and sequenced. The deduced amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry reveals the alpha 6 mRNA to be located within the granule cell layer of the human cerebellar cortex. Recombinant human alpha 6 beta gamma 2S GABAA receptors have been expressed in both stably transfected cells and Xenopus oocytes, and the pharmacology of the benzodiazepine binding site has been determined. The recombinant receptor has a diazepam-insensitive pharmacology, with negligible affinity for a number of classic benzodiazepines. A number of compounds that bind to the benzodiazepine site potentiated the GABA response of alpha 6 beta 2 gamma 2 receptors. Most importantly, the classic benzodiazepine antagonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788) and the partial inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-4513) both acted as agonists at the alpha 6 containing receptor. This observation demonstrates definitively that efficacy of benzodiazepine compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have been reported for these compounds.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zolpidem	Gamma-aminobutyric acid receptor subunit gamma-2	Protein	Humans	Unknown	Agonist	Details

Polypeptides

Name	UniProt ID
Gamma-aminobutyric acid receptor subunit alpha-6	Q16445	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Zolpidem	Gamma-aminobutyric acid receptor subunit alpha-1	Ki (nM)	20.7	N/A	N/A	Details