The Effects of a Novel Anti-arrhythmic Drug, Acehytisine Hydrochloride, on the Human Ether-a-go-go Related Gene K+ Channel and Its Trafficking
The Effects of a Novel Anti-arrhythmic Drug, Acehytisine Hydrochloride, on the Human Ether-a-go-go Related Gene K+ Channel and Its Trafficking
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DOI：
10.1111/j.1742-7843.2008.00357.x
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发表时间：
2009-02-01
影响因子：
3.1
通讯作者：
Pu, Jielin
中科院分区：
文献类型：
--
作者：
Huang, Xingfu;Yang, Yanmin;Pu, Jielin
许多药物通过阻断人类ether-a-go-go相关基因（HERG）K+通道和/或破坏HERG蛋白运输而引起严重的副作用，如长QT综合征。盐酸醋藤碱是一种正在进行IV期临床试验的抗癫痫药物。为了研究盐酸乙酰黑松碱是否影响HERG通道活性和蛋白运输，我们在人胚肾293（HEK 293）细胞中表达HERG，并用全细胞膜片钳技术记录HERG通道电流。我们还通过Western印迹分析测量蛋白水平。我们发现盐酸醋藤碱以浓度依赖的方式抑制HERG阶跃电流（I-HERG）。然而，它对尾电流（I-tail）的影响很小。此外，盐酸醋藤碱加速通道失活并减慢从失活恢复。相反，它不抑制HERG蛋白（135和155 kD）运输，尽管它降低了2500 μ M处的155 kD带密度。此外，在S6结构域的F656 C突变取消了盐酸乙酰海替辛对I-HERG的抑制，并增强了对155 kD带的运输的抑制作用。盐酸醋柳替辛在1000和2500 μ M时阻断HERG蛋白运输。结果表明，盐酸醋柳藤碱对I-HERG有抑制作用，但在1000 μ M以上对I-tail无影响。因此，盐酸醋藤碱可能不会引起QT间期延长，可能是一种有前途的抗心律失常药物，且无严重副作用。
Many drugs cause severe side-effects such as long QT syndromes by blocking the human ether-a-go-go related gene (HERG) K+ channels and/or disrupting HERG protein trafficking. Acehytisine hydrochloride is an anti-arrhythmic drug in phase IV clinical trial. To study whether acehytisine hydrochloride affects HERG channel activity and protein trafficking, we expressed HERG in human embryonic kidney 293 (HEK293) cells and recorded HERG channel currents with a whole-cell patch clamp technique. We also measured the protein levels by Western blot analysis. We found that acehytisine hydrochloride inhibited HERG step current (I-HERG) in a concentration-dependent manner. However, it had little effect on the tail current (I-tail). In addition, acehytisine hydrochloride accelerated channel inactivation and slowed recovery from inactivation. In contrast, it did not inhibit HERG protein (135 and 155 kD) trafficking, although it reduced the 155 kD band density at 2500 mu M. Moreover, the F656C mutation in the S6 domain abolished acehytisine hydrochloride inhibition on the I-HERG and enhanced the inhibitive effects on the trafficking of the 155 kD band. Acehytisine hydrochloride interrupted HERG protein trafficking at 1000 and 2500 mu M. Our data showed that acehytisine hydrochloride could inhibit I-HERG, but had no effects on I-tail until the concentration was above 1000 mu M. Therefore, acehytisine hydrochloride may not induce QT interval prolongation and could be a promising anti-arrhythmic drug without severe side-effects.