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Br J Pharmacol
2000 Oct 01;1314:843-50. doi: 10.1038/sj.bjp.0703558.
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A novel positive allosteric modulator of the GABA(A) receptor: the action of (+)-ROD188.
Thomet U
,
Baur R
,
Razet R
,
Dodd RH
,
Furtmüller R
,
Sieghart W
,
Sigel E
.
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(+)-ROD188 was synthesized in the search for novel ligands of the GABA binding site. It shares some structural similarity with bicuculline. (+)-ROD188 failed to displace [(3)H]-muscimol in binding studies and failed to induce channel opening in recombinant rat alpha1beta2gamma2 GABA(A) receptors functionally expressed in Xenopus oocytes. (+)-ROD188 allosterically stimulated GABA induced currents. Displacement of [(3)H]-Ro15-1788 indicated a low affinity action at the benzodiazepine binding site. In functional studies, stimulation by (+)-ROD188 was little sensitive to the presence of 1 microM of the benzodiazepine antagonist Ro 15-1788, and (+)-ROD188 also stimulated currents mediated by alpha1beta2, indicating a major mechanism of action different from that of benzodiazepines. Allosteric stimulation by (+)-ROD188 was similar in alpha1beta2N265S as in unmutated alpha1beta2, while that by loreclezole was strongly reduced. (+)-ROD188 also strongly stimulated currents elicited by either pentobarbital or 5alpha-pregnan-3alpha-ol-20-one (3alpha-OH-DHP), in line with a mode of action different from that of barbiturates or neurosteroids as channel agonists. Stimulation by (+)-ROD188 was largest in alpha6beta2gamma2 (alpha6beta2gamma2>alpha1beta2gamma2=alpha5beta2gamma2++ +>alpha2beta2ga mma2= alpha3beta2gamma2), indicating a unique subunit isoform specificity. Miniature inhibitory postsynaptic currents (mIPSC) in cultures of rat hippocampal neurons, caused by spontaneous release of GABA showed a prolonged decay time in the presence of 30 microM (+)-ROD188, indicating an enhanced synaptic inhibitory transmission.
Amin,
A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor.
1999, Pubmed
Amin,
A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor.
1999,
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
Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase
Bonnert,
theta, a novel gamma-aminobutyric acid type A receptor subunit.
1999,
Pubmed
,
Xenbase
Buhr,
Subtle changes in residue 77 of the gamma subunit of alpha1beta2gamma2 GABAA receptors drastically alter the affinity for ligands of the benzodiazepine binding site.
1997,
Pubmed
,
Xenbase
Burt,
GABAA receptor subtypes: from pharmacology to molecular biology.
1991,
Pubmed
Chang,
Stoichiometry of a recombinant GABAA receptor.
1996,
Pubmed
,
Xenbase
Chen,
Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA.
1988,
Pubmed
Curtis,
GABA, bicuculline and central inhibition.
1970,
Pubmed
Davies,
Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit.
1997,
Pubmed
Dunn,
Molecular neurobiology of the GABAA receptor.
1994,
Pubmed
Günther,
Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors.
1995,
Pubmed
Hedblom,
A novel class of GABAA receptor subunit in tissues of the reproductive system.
1997,
Pubmed
Holland,
Physiological regulation of the picrotoxin receptor by gamma-butyrolactones and gamma-thiobutyrolactones in cultured hippocampal neurons.
1990,
Pubmed
Holland,
Dual modulation of the gamma-aminobutyric acid type A receptor/ionophore by alkyl-substituted gamma-butyrolactones.
1995,
Pubmed
Horne,
The pharmacology of recombinant GABAA receptors containing bovine alpha 1, beta 1, gamma 2L sub-units stably transfected into mouse fibroblast L-cells.
1992,
Pubmed
Macdonald,
GABAA receptor channels.
1994,
Pubmed
Malgaroli,
Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons.
1992,
Pubmed
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
Nayeem,
Quaternary structure of the native GABAA receptor determined by electron microscopic image analysis.
1994,
Pubmed
Perrais,
Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses.
1999,
Pubmed
Persohn,
Comparative molecular neuroanatomy of cloned GABAA receptor subunits in the rat CNS.
1992,
Pubmed
Pritchett,
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology.
1989,
Pubmed
Rabow,
From ion currents to genomic analysis: recent advances in GABAA receptor research.
1995,
Pubmed
Rassu,
Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes.
1997,
Pubmed
Ryan,
The kinetics of synaptic vesicle recycling measured at single presynaptic boutons.
1993,
Pubmed
Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed
Sigel,
The effect of subunit composition of rat brain GABAA receptors on channel function.
1990,
Pubmed
,
Xenbase
Sigel,
The benzodiazepine binding site of GABAA receptors.
1997,
Pubmed
Sigel,
The antiepileptic drug AWD 131-138 stimulates different recombinant isoforms of the rat GABA(A) receptor through the benzodiazepine binding site.
1998,
Pubmed
,
Xenbase
Sigel,
Properties of single sodium channels translated by Xenopus oocytes after injection with messenger ribonucleic acid.
1987,
Pubmed
,
Xenbase
Stevenson,
beta-Carboline gamma-aminobutyric acidA receptor inverse agonists modulate gamma-aminobutyric acid via the loreclezole binding site as well as the benzodiazepine site.
1995,
Pubmed
,
Xenbase
Thomet,
Dual mode of stimulation by the beta-carboline ZK 91085 of recombinant GABA(A) receptor currents: molecular determinants affecting its action.
1999,
Pubmed
,
Xenbase
Tretter,
Stoichiometry and assembly of a recombinant GABAA receptor subtype.
1997,
Pubmed
Ueno,
Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor.
1997,
Pubmed
Wafford,
A novel allosteric modulatory site on the GABAA receptor beta subunit.
1994,
Pubmed
,
Xenbase
Williams,
Lactone modulation of the gamma-aminobutyric acid A receptor: evidence for a positive modulatory site.
1997,
Pubmed
,
Xenbase
Wingrove,
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.
1994,
Pubmed
,
Xenbase
Wisden,
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon.
1992,
Pubmed
Wooltorton,
Pharmacological and physiological characterization of murine homomeric beta3 GABA(A) receptors.
1997,
Pubmed
,
Xenbase
Zezula,
Interaction of allosteric ligands with GABAA receptors containing one, two, or three different subunits.
1996,
Pubmed
