Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, South Korea.
Eur J Pharmacol. 2011 Aug 1;663(1-3):59-67. doi: 10.1016/j.ejphar.2011.05.006. Epub 2011 May 11.
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.
人 ether-a-go-go 相关基因 (hERG) 心脏 K(+) 通道是开发治疗心血管疾病（如心律失常）药物的代表性药理学靶点之一。人参已被证明具有心脏保护作用。然而，人参皂苷作为人参的有效成分如何与人 hERG K(+) 通道蛋白相互作用的分子机制知之甚少。在本研究中，我们首先通过在非洲爪蟾卵母细胞中表达人 α 亚基来研究各种人参皂苷对 hERG K(+) 通道活性的影响。其中，人参皂苷 Rg(3)（Rg(3)）最有效地增强了外向 I(hERG) 和峰 I(tail)。Rg(3)以浓度和电压依赖性方式诱导大的持久失活尾电流 (I(deactivating-tail))，并显著减慢失活电流衰减。稳态 I(hERG)、峰 I(tail)和持久 I(deactivating-tail)的 EC(50)分别为 0.41±0.05、0.61±0.11 和 0.36±0.04μM。Rg(3)的作用被 hERG K(+) 通道拮抗剂 bepridil 阻断。hERG K(+) 通道中位于通道孔入口处的 S631 突变为 S631C 后，Rg(3)对 hERG K(+) 通道的作用被消除。这些结果表明，hERG K(+) 通道的 S631 残基在 Rg(3)介导的持久 I(deactivating-tail)诱导和 hERG K(+) 通道失活减速中起重要作用。
