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Allosteric modulation of an expressed homo‐oligomeric GABA‐gated chloride channel of Drosophila melanogaster
Author(s) -
Hosie Alastair M.,
Sattelle David B.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16720.x
Subject(s) - gabaa receptor , bicuculline , chemistry , allosteric regulation , long term potentiation , chloride channel , convulsant , gaba receptor antagonist , gamma aminobutyric acid , picrotoxin , biophysics , pharmacology , biochemistry , receptor , biology
1 Functional GABA‐gated chloride channels are formed when cRNA encoding the Drosophila melanogaster GABA receptor subunit RDL is injected into the cytoplasm of Xenopus oocytes. Two‐electrode voltage‐clamp was used to investigate allosteric modulation of GABA‐induced currents recorded from the expressed, bicuculline‐insensitive, RDL homo‐oligomers. 2 Flunitrazepam (0.1 μ m to 100 μ m ) had no effect on the amplitude of responses to 10 μ m GABA (approximately EC 10 ), whereas 4′chlorodiazepam (100 μ m ) enhanced the amplitude of submaximal responses to GABA. 3‐Hydroxymethyl‐β‐carboline (1 μ m ) and ethyl‐β‐carboline‐3‐carboxylate (both 1 and 100 μ m ) had no effect on currents induced by 30 μ m (approximately EC 50 ) GABA. However 100 μ m 3‐hydroxymethyl‐β‐carboline reduced potentiation by 4′chlorodiazepam. 3 The sodium salts of pentobarbitone (10 μ m to 1 mM) and phenobarbitone (50 μ m to 1 mM) dose‐dependently enhanced submaximal GABA responses. Neither barbiturate activated currents in the absence of GABA. 4 At 10 μ m , the steroids 5α‐pregnan‐3α‐ol‐20‐one and alphaxalone (5 α ‐pregnan‐3 α ‐ol‐11,20‐dione), potentiated submaximal GABA responses. The stereoselectivity of steroid action seen on vertebrate GABA A receptors was observed on RDL homo‐oligomers as 5 α ‐pregnan‐3 α ‐ol‐20‐one (10 μ m ) was without effect. None of the three steroids tested activated currents in the absence of GABA. 5 The novel anticonvulsant, loreclezole (100 μ m ), potentiated the response to 10 μ m GABA, but not that of saturating concentrations of GABA. δ‐Hexachlorocyclohexane (0.1 μ m to 30 μ m ) was a potent enhancer of submaximal responses to GABA of RDL. 6 The potencies of barbiturates and steroids on RDL homo‐oligomers resemble those observed for several in situ insect GABA receptors, whereas those of benzodiazepine binding‐site ligands are considerably reduced. The differences in the benzodiazepine pharmacology of RDL homo‐oligomers and native GABA receptors, may reflect roles of other subunits in native insect receptors.