Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
1994 May 10;9110:4569-73.
Show Gene links
Show Anatomy links
The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.
Wingrove PB
,
Wafford KA
,
Bain C
,
Whiting PJ
.
???displayArticle.abstract???
Type A gamma-aminobutyric acid (GABAA) receptors of the mammalian nervous system are a family of ligand-gated ion channels probably formed from the coassembly of different subunits (alpha 1-6, beta 1-3, gamma 1-3, delta) in the arrangement alpha beta gamma or alpha beta delta. The activation of these receptors by GABA can be modulated by a range of compounds acting at distinct allosteric sites. One such compound is the broad-spectrum anticonvulsant loreclezole, which we have recently shown to act via a specific modulatory site on the beta subunit of the GABAA receptor. The action of loreclezole depends on the type of beta subunit present in the receptor complex; receptors containing beta 2 or beta 3 subunits have > 300-fold higher affinity for loreclezole than receptors containing a beta 1 subunit. We have used this property to identify the amino acid residue in the beta subunit that determines the subunit selectivity of loreclezole. Chimeric beta 1/beta 2 human GABAA receptor subunits were constructed and coexpressed in Xenopus oocytes with human alpha 1 and gamma 2s subunits. The chimera beta 1/beta 2Lys237-Gly334 conferred sensitivity to 1 microM loreclezole. Within this region there are four amino acids that are conserved in beta 2 and beta 3 but differ in beta 1. By mutating single amino acids of the beta 1 subunit to the beta 2/beta 3 equivalent, only the beta 1 mutation of Ser-290-->Asn conferred potentiation by loreclezole. Similarly, mutation of the homologous residue in the beta 2 and beta 3 subunits to the beta 1 equivalent (Asn-->Ser) resulted in loss of sensitivity to loreclezole. The affinity for GABA and the potentiation by flunitrazepam were unchanged in receptors containing the mutated beta subunits. Thus, a single amino acid, beta 2 Asn-289 (beta 3 Asn-290), located at the carboxyl-terminal end of the putative channel-lining domain TM2, confers sensitivity to the modulatory effects of loreclezole.
Ashton,
In vivo studies on the mechanism of action of the broad spectrum anticonvulsant loreclezole.
1992, Pubmed
Ashton,
In vivo studies on the mechanism of action of the broad spectrum anticonvulsant loreclezole.
1992,
Pubmed
Burt,
GABAA receptor subtypes: from pharmacology to molecular biology.
1991,
Pubmed
Changeux,
The functional architecture of the acetylcholine nicotinic receptor explored by affinity labelling and site-directed mutagenesis.
1992,
Pubmed
Doble,
Multiple benzodiazepine receptors: no reason for anxiety.
1992,
Pubmed
Duggan,
Quantitative immunoprecipitation studies with anti-gamma-aminobutyric acidA receptor gamma 2 1-15 Cys antibodies.
1992,
Pubmed
Grenningloh,
Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes.
1990,
Pubmed
,
Xenbase
Grenningloh,
Cloning and expression of the 58 kd beta subunit of the inhibitory glycine receptor.
1990,
Pubmed
,
Xenbase
Hadingham,
Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.
1993,
Pubmed
Hadingham,
Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors.
1993,
Pubmed
,
Xenbase
Herb,
The third gamma subunit of the gamma-aminobutyric acid type A receptor family.
1992,
Pubmed
Im,
Potentiation of gamma-aminobutyric acid-induced chloride currents by various benzodiazepine site agonists with the alpha 1 gamma 2, beta 2 gamma 2 and alpha 1 beta 2 gamma 2 subtypes of cloned gamma-aminobutyric acid type A receptors.
1993,
Pubmed
Laurie,
The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development.
1992,
Pubmed
Maricq,
Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel.
1991,
Pubmed
,
Xenbase
McKernan,
GABAA receptor subtypes immunopurified from rat brain with alpha subunit-specific antibodies have unique pharmacological properties.
1991,
Pubmed
Noda,
Structural homology of Torpedo californica acetylcholine receptor subunits.
1983,
Pubmed
Pritchett,
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology.
1989,
Pubmed
Pritchett,
Type I and type II GABAA-benzodiazepine receptors produced in transfected cells.
1989,
Pubmed
Pritchett,
gamma-Aminobutyric acid type A receptor point mutation increases the affinity of compounds for the benzodiazepine site.
1991,
Pubmed
Schofield,
Sequence and expression of human GABAA receptor alpha 1 and beta 1 subunits.
1989,
Pubmed
Seeburg,
The GABAA receptor family: molecular and functional diversity.
1990,
Pubmed
Shivers,
Two novel GABAA receptor subunits exist in distinct neuronal subpopulations.
1989,
Pubmed
Stephenson,
The gamma 2 subunit is an integral component of the gamma-aminobutyric acidA receptor but the alpha 1 polypeptide is the principal site of the agonist benzodiazepine photoaffinity labeling reaction.
1990,
Pubmed
Unwin,
Nicotinic acetylcholine receptor at 9 A resolution.
1993,
Pubmed
Wafford,
Ethanol potentiation of GABAA receptors requires phosphorylation of the alternatively spliced variant of the gamma 2 subunit.
1992,
Pubmed
,
Xenbase
Wafford,
Functional comparison of the role of gamma subunits in recombinant human gamma-aminobutyric acidA/benzodiazepine receptors.
1993,
Pubmed
,
Xenbase
Wafford,
Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant gamma-aminobutyric acidA receptor subtypes.
1993,
Pubmed
,
Xenbase
Wagstaff,
The GABAA receptor beta 3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7.
1991,
Pubmed
Whiting,
Another mechanism for creating diversity in gamma-aminobutyrate type A receptors: RNA splicing directs expression of two forms of gamma 2 phosphorylation site.
1990,
Pubmed
Wieland,
A single histidine in GABAA receptors is essential for benzodiazepine agonist binding.
1992,
Pubmed
Wisden,
GABAA receptor channels: from subunits to functional entities.
1992,
Pubmed
