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
2004 May 18;10120:7769-74. doi: 10.1073/pnas.0400220101.
Show Gene links
Show Anatomy links
Positioning of the alpha-subunit isoforms confers a functional signature to gamma-aminobutyric acid type A receptors.
Minier F
,
Sigel E
.
???displayArticle.abstract???
Fast synaptic inhibitory transmission in the CNS is mediated by gamma-aminobutyric acid type A (GABA(A)) receptors. They belong to the ligand-gated ion channel receptor superfamily, and are constituted of five subunits surrounding a chloride channel. Their clinical interest is highlighted by the number of therapeutic drugs that act on them. It is well established that the subunit composition of a receptor subtype determines its pharmacological properties. We have investigated positional effects of two different alpha-subunit isoforms, alpha(1) and alpha(6), in a single pentamer. For this purpose, we used concatenated subunit receptors in which subunit arrangement is predefined. The resulting receptors were expressed in Xenopus oocytes and analyzed by using the two-electrode voltage-clamp technique. Thus, we have characterized gamma(2)beta(2)alpha(1)beta(2)alpha(1), gamma(2)beta(2)alpha(6)beta(2)alpha(6), gamma(2)beta(2)alpha(1)beta(2)alpha(6), and gamma(2)beta(2)alpha(6)beta(2)alpha(1) GABA(A) receptors. We investigated their response to the agonist GABA, to the partial agonist piperidine-4-sulfonic acid, to the noncompetitive inhibitor furosemide and to the positive allosteric modulator diazepam. Each receptor isoform is characterized by a specific set of properties. In this case, subunit positioning provides a functional signature to the receptor. We furthermore show that a single alpha(6)-subunit is sufficient to confer high furosemide sensitivity, and that the diazepam efficacy is determined exclusively by the alpha-subunit neighboring the gamma(2)-subunit. By using this diagnostic tool, it should become possible to determine the subunit arrangement of receptors expressed in vivo that contain alpha(1)- and alpha(6)-subunits. This method may also be applied to the study of other ion channels.
Backus,
Stoichiometry of a recombinant GABAA receptor deduced from mutation-induced rectification.
1993, Pubmed
Backus,
Stoichiometry of a recombinant GABAA receptor deduced from mutation-induced rectification.
1993,
Pubmed
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998,
Pubmed
Baumann,
Individual properties of the two functional agonist sites in GABA(A) receptors.
2003,
Pubmed
,
Xenbase
Baumann,
Subunit arrangement of gamma-aminobutyric acid type A receptors.
2001,
Pubmed
,
Xenbase
Baumann,
Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement.
2002,
Pubmed
,
Xenbase
Benke,
Distribution, prevalence, and drug binding profile of gamma-aminobutyric acid type A receptor subtypes differing in the beta-subunit variant.
1994,
Pubmed
Boileau,
The relative amount of cRNA coding for gamma2 subunits affects stimulation by benzodiazepines in GABA(A) receptors expressed in Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Boileau,
Effects of gamma2S subunit incorporation on GABAA receptor macroscopic kinetics.
2003,
Pubmed
,
Xenbase
Chang,
Stoichiometry of a recombinant GABAA receptor.
1996,
Pubmed
,
Xenbase
Davies,
Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit.
1997,
Pubmed
Ebert,
Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human gamma-aminobutyric acid type A receptors.
1997,
Pubmed
,
Xenbase
Ebert,
Molecular pharmacology of gamma-aminobutyric acid type A receptor agonists and partial agonists in oocytes injected with different alpha, beta, and gamma receptor subunit combinations.
1994,
Pubmed
,
Xenbase
Farrar,
Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer.
1999,
Pubmed
Hansen,
Effects of GABA(A) receptor partial agonists in primary cultures of cerebellar granule neurons and cerebral cortical neurons reflect different receptor subunit compositions.
2001,
Pubmed
,
Xenbase
Hedblom,
A novel class of GABAA receptor subunit in tissues of the reproductive system.
1997,
Pubmed
Hevers,
Pharmacological heterogeneity of gamma-aminobutyric acid receptors during development suggests distinct classes of rat cerebellar granule cells in situ.
2002,
Pubmed
Jechlinger,
Subunit composition and quantitative importance of hetero-oligomeric receptors: GABAA receptors containing alpha6 subunits.
1998,
Pubmed
Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed
Khan,
The alpha 1 and alpha 6 subunits can coexist in the same cerebellar GABAA receptor maintaining their individual benzodiazepine-binding specificities.
1996,
Pubmed
Korpi,
Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor.
1995,
Pubmed
,
Xenbase
Laurie,
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum.
1992,
Pubmed
Leao,
Tonic benzodiazepine-sensitive GABAergic inhibition in cultured rodent cerebellar granule cells.
2000,
Pubmed
Lolait,
Cloning and expression of a novel rat GABAA receptor.
1989,
Pubmed
,
Xenbase
Lüddens,
Cerebellar GABAA receptor selective for a behavioural alcohol antagonist.
1990,
Pubmed
Macdonald,
GABAA receptor channels.
1994,
Pubmed
Malherbe,
GABAA-receptor expressed from rat brain alpha- and beta-subunit cDNAs displays potentiation by benzodiazepine receptor ligands.
1990,
Pubmed
,
Xenbase
Malherbe,
Functional characteristics and sites of gene expression of the alpha 1, beta 1, gamma 2-isoform of the rat GABAA receptor.
1990,
Pubmed
,
Xenbase
Mathews,
Developmental alteration in GABAA receptor structure and physiological properties in cultured cerebellar granule neurons.
1994,
Pubmed
McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed
Nusser,
Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells.
1998,
Pubmed
Pollard,
Quantitative characterization of alpha 6 and alpha 1 alpha 6 subunit-containing native gamma-aminobutyric acidA receptors of adult rat cerebellum demonstrates two alpha subunits per receptor oligomer.
1995,
Pubmed
Pöltl,
Subunit composition and quantitative importance of GABA(A) receptor subtypes in the cerebellum of mouse and rat.
2003,
Pubmed
Rabow,
From ion currents to genomic analysis: recent advances in GABAA receptor research.
1995,
Pubmed
Rudolph,
GABA(A) receptor subtypes: dissecting their pharmacological functions.
2001,
Pubmed
Saxena,
Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms.
1996,
Pubmed
Sieghart,
Subunit composition, distribution and function of GABA(A) receptor subtypes.
2002,
Pubmed
Sigel,
Electrophysiological evidence for the coexistence of alpha1 and alpha6 subunits in a single functional GABA(A) receptor.
2000,
Pubmed
,
Xenbase
Sigel,
Properties of single sodium channels translated by Xenopus oocytes after injection with messenger ribonucleic acid.
1987,
Pubmed
,
Xenbase
Thompson,
Residues in transmembrane domains I and II determine gamma-aminobutyric acid type AA receptor subtype-selective antagonism by furosemide.
1999,
Pubmed
,
Xenbase
Tia,
Developmental changes of inhibitory synaptic currents in cerebellar granule neurons: role of GABA(A) receptor alpha 6 subunit.
1996,
Pubmed
Tretter,
Stoichiometry and assembly of a recombinant GABAA receptor subtype.
1997,
Pubmed
Wall,
Furosemide reveals heterogeneous GABA(A) receptor expression at adult rat Golgi cell to granule cell synapses.
2002,
Pubmed
Wall,
Competitive GABA(A) receptor antagonists increase the proportion of functional high-affinity alpha6 subunit-containing receptors in granule cells of adult rat cerebellum.
2003,
Pubmed
Whiting,
Neuronally restricted RNA splicing regulates the expression of a novel GABAA receptor subunit conferring atypical functional properties [corrected; erratum to be published].
1997,
Pubmed
,
Xenbase
Whiting,
Molecular and functional diversity of the expanding GABA-A receptor gene family.
1999,
Pubmed
Wisden,
Ectopic expression of the GABA(A) receptor alpha6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition.
2002,
Pubmed
Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
