title: Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism.
abstract: Extracts of the pepper plant kava (Piper methysticum) are effective in alleviating anxiety in clinical trials. Despite the long-standing therapeutic interest in kava, the molecular target(s) of the pharmacologically active constituents, kavalactones have not been established. γ-Aminobutyric acid type A receptors (GABAARs) are assumed to be the in vivo molecular target of kavalactones based on data from binding assays, but evidence in support of a direct interaction between kavalactones and GABAARs is scarce and equivocal. In this study, we characterised the functional properties of the major anxiolytic kavalactone, kavain at human recombinant α1β2, β2γ2L, αxβ2γ2L (x = 1, 2, 3 and 5), α1βxγ2L (x = 1, 2 and 3) and α4β2δ GABAARs expressed in Xenopus oocytes using the two-electrode voltage clamp technique. We found that kavain positively modulated all receptors regardless of the subunit composition, but the degree of enhancement was greater at α4β2δ than at α1β2γ2L GABAARs. The modulatory effect of kavain was unaffected by flumazenil, indicating that kavain did not enhance GABAARs via the classical benzodiazepine binding site. The β3N265M point mutation which has been previously shown to profoundly decrease anaesthetic sensitivity, also diminished kavain-mediated potentiation. To our knowledge, this study is the first report of the functional characteristics of a single kavalactone at distinct GABAAR subtypes, and presents the first experimental evidence in support of a direct interaction between a kavalactone and GABAARs.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Han Chow
authors.initials: HC
authors.lastname: Chua
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.|Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Emilie T H
authors.initials: ET
authors.lastname: Christensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoestgaard-Jensen
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Leonny Y
authors.initials: LY
authors.lastname: Hartiadi
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ramzan
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Absalom
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D005045:Etomidate / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D006801:Humans; D020901:Kava / Q000737:chemistry*; D009154:Mutation / Q000235:genetics; D015742:Propofol / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000777:Anesthetics; D014151:Anti-Anxiety Agents; D021122:Protein Subunits; D011753:Pyrones; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D003975:Diazepam; C011889:kavain; D015742:Propofol; D005045:Etomidate