Curcumol allosterically modulates GABA(A) receptors in a manner distinct from benzodiazepines

Inhibitory A type γ-aminobutyric acid receptors (GABA_ARs) 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 GABA_ARs 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 GABA_AR, curcumol failed to further enhance GABA-induced currents, suggesting shared mechanisms underlying these two agents on GABA_ARs. 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 GABA_ARs by curcumol and menthol, or diazepam, respectively. Curcumol may therefore exert its actions on GABA_ARs at sites distinct from benzodiazepine sites. These findings shed light on the future development of new therapeutics drugs targeting GABA_ARs.