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Allosteric modulators affect the efficacy of partial agonists for recombinant GABA(A) receptors.
Maksay G
,
Thompson SA
,
Wafford KA
.
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Different alpha subunits of human gamma-aminobutyric acid type A (GABA(A)) receptors were transiently expressed together with beta(3) and gamma(2) subunits in Xenopus oocytes to examine the interactions of various GABA(A) agonists and representative allosteric modulators. Chloride currents elicited by agonists were measured using two electrode voltage clamp electrophysiology. Where compounds behaved as full agonists, i.e. GABA on all subtypes and 4,5,6, 7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP) on alpha2beta(3)gamma(2) GABA(A) receptors, agonist concentration-response curves were shifted to the left by the benzodiazepine full agonist chlordiazepoxide and the anticonvulsant loreclezole, or to the right by the inverse agonist 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester (DMCM), with no effect on the maximal currents (I(max)). In contrast, maximal responses for different partial GABA(A) agonists on all benzodiazepine-sensitive alpha(x)beta(3)gamma(2) GABA(A) receptors were enhanced by chlordiazepoxide. I(max) values for piperidine-4-sulphonic acid (P4S) on alpha(1)beta(3)gamma(2), THIP on alpha(3)beta(3)gamma(2), and 5-(4-piperidyl)isothiazol-3-ol (thio-4-PIOL) on alpha(2)beta(3)gamma(2) and alpha(5)beta(3)gamma(2) GABA(A) receptors were increased by chlordiazepoxide, while that for P4S on alpha(1)beta(3)gamma(2) receptors was decreased by DMCM. The I(max) values for partial agonists were also enhanced by pentobarbitone, the neurosteroid allopregnanolone and loreclezole irrespective of receptor subtype or the nature of the partial agonist. In the light of models of ligand-gated ion channel receptor activation we suggest two possible mechanisms of action for the effects of allosteric modulators on partial agonist receptor activation: either selective modulation of agonist affinity for the open/closed state, or direct modulation of the gating process itself.
Akaike,
gamma-Aminobutyric-acid- and pentobarbitone-gated chloride currents in internally perfused frog sensory neurones.
1985, Pubmed
Akaike,
gamma-Aminobutyric-acid- and pentobarbitone-gated chloride currents in internally perfused frog sensory neurones.
1985,
Pubmed
Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase
Barker,
GABA analogues activate channels of different duration on cultured mouse spinal neurons.
1981,
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
Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed
Donnelly,
Loreclezole enhances apparent desensitization of recombinant GABAA receptor currents.
1996,
Pubmed
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
Ebert,
Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human gamma-aminobutyric acid type A receptors.
1997,
Pubmed
,
Xenbase
Galzi,
The multiple phenotypes of allosteric receptor mutants.
1996,
Pubmed
Jones,
Defining affinity with the GABAA receptor.
1998,
Pubmed
Krause,
Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor.
1998,
Pubmed
,
Xenbase
Lavoie,
Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on alpha-subunit isoform.
1997,
Pubmed
MacDonald,
Kinetic properties and regulation of GABAA receptor channels.
1992,
Pubmed
Neelands,
Spontaneous and gamma-aminobutyric acid (GABA)-activated GABA(A) receptor channels formed by epsilon subunit-containing isoforms.
1999,
Pubmed
Puia,
Neurosteroids act on recombinant human GABAA receptors.
1990,
Pubmed
Serfozo,
Effect of a benzodiazepine (chlordiazepoxide) on a GABAA receptor from rat brain. Requirement of only one bound GABA molecule for channel opening.
1992,
Pubmed
Sigel,
The benzodiazepine binding site of GABAA receptors.
1997,
Pubmed
Sigel,
Allosteric modulation by benzodiazepine receptor ligands of the GABAA receptor channel expressed in Xenopus oocytes.
1988,
Pubmed
,
Xenbase
Thompson,
Mutation at the putative GABA(A) ion-channel gate reveals changes in allosteric modulation.
1999,
Pubmed
,
Xenbase
Thompson,
Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination.
1996,
Pubmed
,
Xenbase
Tretter,
Stoichiometry and assembly of a recombinant GABAA receptor subtype.
1997,
Pubmed
Turner,
Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus.
1989,
Pubmed
Wafford,
Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant gamma-aminobutyric acidA receptor subtypes.
1993,
Pubmed
,
Xenbase
Wafford,
Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit.
1996,
Pubmed
,
Xenbase
Wafford,
A novel allosteric modulatory site on the GABAA receptor beta subunit.
1994,
Pubmed
,
Xenbase
Woodward,
Effects of steroids on gamma-aminobutyric acid receptors expressed in Xenopus oocytes by poly(A)+ RNA from mammalian brain and retina.
1992,
Pubmed
,
Xenbase
Yakushiji,
Differential properties of type I and type II benzodiazepine receptors in mammalian CNS neurones.
1993,
Pubmed
Zhong,
Interactions between loreclezole, chlormethiazole and pentobarbitone at GABA(A) receptors: functional and binding studies.
1997,
Pubmed
