Chae Yun Ju, Jeon Ji Hyun, Lee Hong Joon, Kim In-Beom, Choi Jin-Sung, Sung Ki-Wug, Hahn Sang June
Department of Physiology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, 224 Banpo-daero, Seocho-gu, Seoul, 137-701, Korea.
Naunyn Schmiedebergs Arch Pharmacol. 2014 Jan;387(1):23-32. doi: 10.1007/s00210-013-0911-y. Epub 2013 Sep 18.
Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active S-enantiomer of the racemic mixture of RS-citalopram and is widely used in the treatment of depression. The effects of escitalopram and citalopram on the human ether-a-go-go-related gene (hERG) channels expressed in human embryonic kidney cells were investigated using voltage-clamp and Western blot analyses. Both drugs blocked hERG currents in a concentration-dependent manner with an IC50 value of 2.6 μM for escitalopram and an IC50 value of 3.2 μM for citalopram. The blocking of hERG by escitalopram was voltage-dependent, with a steep increase across the voltage range of channel activation. However, voltage independence was observed over the full range of activation. The blocking by escitalopram was frequency dependent. A rapid application of escitalopram induced a rapid and reversible blocking of the tail current of hERG. The extent of the blocking by escitalopram during the depolarizing pulse was less than that during the repolarizing pulse, suggesting that escitalopram has a high affinity for the open state of the hERG channel, with a relatively lower affinity for the inactivated state. Both escitalopram and citalopram produced a reduction of hERG channel protein trafficking to the plasma membrane but did not affect the short-term internalization of the hERG channel. These results suggest that escitalopram blocked hERG currents at a supratherapeutic concentration and that it did so by preferentially binding to both the open and the inactivated states of the channels and by inhibiting the trafficking of hERG channel protein to the plasma membrane.
艾司西酞普兰是一种选择性5-羟色胺再摄取抑制剂，是消旋体RS-西酞普兰的药理活性S-对映体，广泛用于治疗抑郁症。采用电压钳和蛋白质免疫印迹分析，研究了艾司西酞普兰和西酞普兰对人胚胎肾细胞中表达的人醚-去极化相关基因（hERG）通道的影响。两种药物均以浓度依赖性方式阻断hERG电流，艾司西酞普兰的半数抑制浓度（IC50）值为2.6μM，西酞普兰的IC50值为3.2μM。艾司西酞普兰对hERG的阻断具有电压依赖性，在通道激活的电压范围内急剧增加。然而，在整个激活范围内观察到电压非依赖性。艾司西酞普兰的阻断具有频率依赖性。快速应用艾司西酞普兰可诱导hERG尾电流快速且可逆的阻断。去极化脉冲期间艾司西酞普兰的阻断程度小于复极化脉冲期间，这表明艾司西酞普兰对hERG通道的开放状态具有高亲和力，而对失活状态的亲和力相对较低。艾司西酞普兰和西酞普兰均使hERG通道蛋白向质膜的转运减少，但不影响hERG通道的短期内化。这些结果表明，艾司西酞普兰在超治疗浓度下阻断hERG电流，其机制是优先结合通道的开放状态和失活状态，并抑制hERG通道蛋白向质膜的转运。
