Abstract
Inhibitory A type γ-aminobutyric acid receptors (GABAARs) play a pivotal role in orchestrating various brain functions and represent an important molecular target in neurological and psychiatric diseases, necessitating the need for the discovery and development of novel modulators. Here, we show that a natural compound curcumol, acts as an allosteric enhancer of GABAARs in a manner distinct from benzodiazepines. Curcumol markedly facilitated GABA-activated currents and shifted the GABA concentration-response curve to the left in cultured hippocampal neurons. When co-applied with the classical benzodiazepine diazepam, curcumol further potentiated GABA-induced currents. In contrast, in the presence of a saturating concentration of menthol, a positive modulator for GABAAR, curcumol failed to further enhance GABA-induced currents, suggesting shared mechanisms underlying these two agents on GABAARs. Moreover, the benzodiazepine antagonist flumazenil did not alter the enhancement of GABA response by curcumol and menthol, but abolished that by DZP. Finally, mutations at the β2 or γ2 subunit predominantly eliminated modulation of recombinant GABAARs by curcumol and menthol, or diazepam, respectively. Curcumol may therefore exert its actions on GABAARs at sites distinct from benzodiazepine sites. These findings shed light on the future development of new therapeutics drugs targeting GABAARs.
Highlights
The γ-aminobutyric acid (GABA) system is essential for the orchestration of local networks and the functional interaction between different brain regions[1]
GABAARs, here we identify that curcumol as an allosteric modulator of GABAARs in a manner distinct from benzodiazepines, but through sites shared with menthol
The Hill coefficients in the absence or presence of curcumol were 2.0 ± 0.6 and 1.9 ± 0.3, respectively. This increase of the apparent affinity to GABA implies a potentially allosteric regulation by curcumol of GABA-mediated GABAAR response; the precise mechanisms underlying the action of curcumol on GABAARs remain not fully understood
Summary
The γ-aminobutyric acid (GABA) system is essential for the orchestration of local networks and the functional interaction between different brain regions[1]. First isolated from plants used as tranquilizers in folkloric medicine, together with their synthetic derivatives, possess selective affinity for the benzodiazepine-binding site of GABAARs with a broad spectrum of central nervous system effects[30]. The widely-used cooling and flavouring agent menthol (5-methyl-2-propan-2-ylcyclohexan-1-ol, Fig. 1a), the best-known monoterpene extracted from the essential oil of the genus Mentha of the Lamiaceae family, suppresses hippocampal neuronal excitation and epileptic activity by enhancing GABAergic inhibition[37]. Curcumol38 [(3 S,5 S,6 S,8aS)-3-methyl-8-methylidene-5(propan-2-yl)octahydro-6H-3a,6-epoxyazulen-6-ol] is a sesquiterpene compound and a major bioactive component of Rhizoma Curcumae oil It induces minimal activation of GABAARs on its own, but facilitates the GABA-activated current in hippocampal neurons and cell lines, which express endogenous and recombinant GABAARs33, respectively. GABAARs, here we identify that curcumol as an allosteric modulator of GABAARs in a manner distinct from benzodiazepines, but through sites shared with menthol
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