Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism.

Han Chow Chua,Leonny Y Hartiadi,Kirsten Hoestgaard-Jensen,Anders A Jensen,Iqbal Ramzan,Emilie T H Christensen,Mary Chebib,Nathan L Absalom,Steven Barnes

doi:10.1371/journal.pone.0157700

Han Chow Chua, Leonny Y Hartiadi + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0157700

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Journal: PloS one	Publication Date: Jun 22, 2016
Citations: 63	License type: CC BY 4.0

Affiliation: University of Sydney, University of Copenhagen

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.

Highlights

The use of intoxicating substances to enhance mood, alter consciousness and to achieve spiritual enlightenment is known in virtually every culture
We demonstrate that the modulatory effect of kavain at GABAARs occurs in a subtype non-selective and flumazenil-insensitive manner
Our results demonstrated that kavain potentiation did not require the α1 or γ2L subunit, as both β2γ2L and α1β2 GABAARs were modulated to similar extent as α1β2γ2L GABAARs

Summary

Introduction

The use of intoxicating substances to enhance mood, alter consciousness and to achieve spiritual enlightenment is known in virtually every culture. Functional Characterisation of Kavain at GABAA Receptors have been using the root of a native pepper plant called kava (Piper methysticum) to prepare a non-alcoholic psychoactive beverage, which is called kava. Kava drinking is an integral component of the Pacific Islander culture, with kava playing roles as a sacred drug in religious rituals, a social lubricant at formal gatherings, and a medicine to induce relaxation and sleep [2]. The contemporary use of kava extends beyond ritualised circumstances [3, 4]. The recreational use of kava as a substitute for alcohol is gaining popularity owing to kava’s calming effect which contrasts the aggressive tendencies associated with alcohol [6]

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