Wu Wei, Gardner Alison, Sachse Frank B, Sanguinetti Michael C
Nora Eccles Harrison Cardiovascular Research and Training Institute (W.W., A.G., F.B.S., M.C.S.), Department of Bioengineering (F.B.S.), Department of Internal Medicine, Division of Cardiovascular Medicine (M.C.S.), University of Utah, Salt Lake City, Utah.
Nora Eccles Harrison Cardiovascular Research and Training Institute (W.W., A.G., F.B.S., M.C.S.), Department of Bioengineering (F.B.S.), Department of Internal Medicine, Division of Cardiovascular Medicine (M.C.S.), University of Utah, Salt Lake City, Utah
Mol Pharmacol. 2016 Oct;90(4):469-82. doi: 10.1124/mol.116.104091. Epub 2016 Aug 8.
Ginsenoside 20(S)-Rg3 (Rg3) is a steroid glycoside that induces human ether-à-go-go-related gene type 1 (hERG1, Kv11.1) channels to activate at more negative potentials and to deactivate more slowly than normal. However, it is unknown whether this action is unique to hERG1 channels. Here we compare and contrast the mechanisms of actions of Rg3 on hERG1 with three other members of the ether-à-go-go (EAG) K(+) channel gene family, including EAG1 (Kv10.1), ERG3 (Kv11.3), and ELK1 (Kv12.1). All four channel types were heterologously expressed in Xenopus laevis oocytes, and K(+) currents were measured using the two-microelectrode voltage-clamp technique. At a maximally effective concentration, Rg3 shifted the half-point of voltage-dependent activation of currents by -14 mV for ERG1 (EC50 = 414 nM), -20 mV for ERG3 (EC50 = 374 nM), -28 mV for EAG1 (EC50 = 1.18 μM), and more than -100 mV for ELK1 (EC50 = 197 nM) channels. Rg3 also induced slowing of ERG1, ERG3, and ELK1 channel deactivation and accelerated the rate of EAG1 channel activation. A Markov model was developed to simulate gating and the effects of Rg3 on the voltage dependence of activation of hELK1 channels. Understanding the mechanism underlying the action of Rg3 may facilitate the development of more potent and selective EAG family channel activators as therapies for cardiovascular and neural disorders.
人参皂苷20(S)-Rg3（Rg3）是一种甾体糖苷，它可诱导人类醚-去极化相关基因1型（hERG1，Kv11.1）通道在更负的电位下激活，且失活比正常情况更慢。然而，尚不清楚这种作用是否为hERG1通道所特有。在此，我们比较并对比了Rg3对hERG1与醚-去极化（EAG）钾通道基因家族的其他三个成员（包括EAG1（Kv10.1）、ERG3（Kv11.3）和ELK1（Kv12.1））的作用机制。所有四种通道类型均在非洲爪蟾卵母细胞中进行异源表达，并使用双电极电压钳技术测量钾电流。在最大有效浓度下，Rg3使ERG1（EC50 = 414 nM）电流的电压依赖性激活半值点负移14 mV，使ERG3（EC50 = 374 nM）负移20 mV，使EAG1（EC50 = 1.18 μM）负移28 mV，使ELK1（EC50 = 197 nM）通道负移超过100 mV。Rg3还诱导ERG1、ERG3和ELK1通道失活减慢，并加速EAG1通道的激活速率。开发了一个马尔可夫模型来模拟门控以及Rg3对hELK1通道激活电压依赖性的影响。了解Rg3作用的潜在机制可能有助于开发更有效和更具选择性的EAG家族通道激活剂，作为心血管和神经疾病的治疗方法。
