title: Ginsenoside Rg(3) decelerates hERG K(+) channel deactivation through Ser631 residue interaction.
abstract: The human ether-a-go-go-related gene (hERG) cardiac K(+) channels are one of the representative pharmacological targets for development of drugs against cardiovascular diseases such as arrhythmia. Panax ginseng has been known to have cardio-protective effects. However, little is known about the molecular mechanisms of how ginsenosides, the active ingredients in Panax ginseng, interact with hERG K(+) channel proteins. In the present study, we first examined the effects of various ginsenosides on hERG K(+) channel activity by expressing human α subunits in Xenopus oocytes. Among them ginsenoside Rg(3) (Rg(3)) most potently enhanced outward I(hERG) and peak I(tail). Rg(3) induced a large persistent deactivating-tail current (I(deactivating-tail)) and profoundly decelerated deactivating current decay in both concentration- and voltage-dependent manners. The EC(50) for steady-state I(hERG), peak I(tail), and persistent I(deactivating-tail) was 0.41±0.05, 0.61±0.11, and 0.36±0.04μM, respectively. Rg(3) actions were blocked by bepridil, a hERG K(+) channel antagonist. Site-directed mutation of S631, which is located at the channel pore entryway, to S631C in hERG K(+) channel abolished Rg(3) actions on hERG K(+) channels. These results indicate that S631 residue of hERG K(+) channel plays an important role in Rg(3)-mediated induction of a persistent I(deactivating-tail) and in a deceleration of hERG K(+) channel deactivation.
authors.affiliation: Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, South Korea.
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Choi
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Shin
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Byung-Hwan
authors.initials: BH
authors.lastname: Lee
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kang
authors.forename: Hyeon-Joong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D036145:Ginsenosides / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D012694:Serine
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D036145:Ginsenosides; C000606913:KCNH2 protein, human; C097367:ginsenoside Rg3; D012694:Serine