title: Flavonoid Myricetin Modulates GABA(A) Receptor Activity through Activation of Ca(2+) Channels and CaMK-II Pathway.
abstract: The flavonoid myricetin is found in several sedative herbs, for example, the St. John's Wort, but its influence on sedation and its possible mechanism of action are unknown. Using patch-clamp technique on a brain slice preparation, the present study found that myricetin promoted GABAergic activity in the neurons of hypothalamic paraventricular nucleus (PVN) by increasing the decay time and frequency of the inhibitory currents mediated by GABA(A) receptor. This effect of myricetin was not blocked by the GABA(A) receptor benzodiazepine- (BZ-) binding site antagonist flumazenil, but by KN-62, a specific inhibitor of the Ca(2+)/calmodulin-stimulated protein kinase II (CaMK-II). Patch clamp and live Ca(2+) imaging studies found that myricetin could increase Ca(2+) current and intracellular Ca(2+) concentration, respectively, via T- and L-type Ca(2+) channels in rat PVN neurons and hypothalamic primary culture neurons. Immunofluorescence staining showed increased phosphorylation of CaMK-II after myricetin incubation in primary culture of rat hypothalamic neurons, and the myricetin-induced CaMK-II phosphorylation was further confirmed by Western blotting in PC-12 cells. The present results suggest that myricetin enhances GABA(A) receptor activity via calcium channel/CaMK-II dependent mechanism, which is distinctively different from that of most existing BZ-binding site agonists of GABA(A) receptor.
authors.affiliation: Epithelial Cell Biology Research Centre, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Xiao Hu
authors.initials: XH
authors.lastname: Zhang
authors.forename: Ze Gang
authors.initials: ZG
authors.lastname: Ma
authors.forename: Dewi Kenneth
authors.initials: DK
authors.lastname: Rowlands
authors.forename: Yu Lin
authors.initials: YL
authors.lastname: Gou
authors.forename: Kin Lam
authors.initials: KL
authors.lastname: Fok
authors.forename: Hau Yan
authors.initials: HY
authors.lastname: Wong
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Yu
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.forename: Li
authors.initials: L
authors.lastname: Mu
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Wing Ho
authors.initials: WH
authors.lastname: Yung
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Chung
authors.forename: Bei Lin
authors.initials: BL
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan