title: The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator.
abstract: Stiripentol (STP) has been used as co-therapy for treatment of epilepsy for many years. Its mechanism of action has long been considered to be indirect, as it inhibits the enzymes responsible for metabolism of other anti-convulsant agents. However, a recent report suggested that STP might also act at the neuronal level, increasing inhibitory GABAergic neurotransmission. We examined the effect of STP on the functional properties of recombinant GABA(A) receptors (GABARs) and found that it was a positive allosteric modulator of these ion channels. Its activity showed some dependence on subunit composition, with greater potentiation of alpha3-containing receptors and reduced potentiation when the beta1 or epsilon subunits were present. STP caused a leftward shift in the GABA concentration-response relationship, but did not increase the peak response of the receptors to a maximal GABA concentration. Although STP shares some functional characteristics with the neurosteroids, its activity was not inhibited by a neurosteroid site antagonist and was unaffected by a mutation in the alpha3 subunit that reduced positive modulation by neurosteroids. The differential effect of STP on beta1- and beta2/beta3-containing receptors was not altered by mutations within the second transmembrane domain that affect modulation by loreclezole. These findings suggest that STP acts as a direct allosteric modulator of the GABAR at a site distinct from many commonly used anti-convulsant, sedative and anxiolytic drugs. Its higher activity at alpha3-containing receptors as well as its activity at delta-containing receptors may provide a unique opportunity to target selected populations of GABARs.
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA. jfisher@gw.med.sc.edu
authors.forename: Janet L
authors.initials: JL
authors.lastname: Fisher
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003975:Diazepam / Q000494:pharmacology; D004148:Dioxolanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D017354:Point Mutation / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; C021092:stiripentol