Lee Hong Joon, Choi Jin-Sung, Choi Bok Hee, Hahn Sang June
Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea.
Naunyn Schmiedebergs Arch Pharmacol. 2017 Jun;390(6):633-642. doi: 10.1007/s00210-017-1364-5. Epub 2017 Mar 6.
Risperidone and one of its active metabolites, paliperidone, are widely used for the treatment of schizophrenia. We used a patch-clamp study to investigate the effects of paliperidone on hERG potassium channels expressed in HEK cells. Western blot analyses were used to study the effects of risperidone and paliperidone on hERG and hERG 3.1 isoform channel trafficking. Risperidone and paliperidone inhibited the hERG tail currents in a concentration-dependent manner with IC values of 0.16 and 0.57 μM, respectively. The block of hERG currents by paliperidone was voltage-dependent, increasing over a range of voltages for channel activation. A fast application of paliperidone inhibited the hERG current elicited by a 5-s depolarizing pulse to +60 mV to fully inactivate the hERG currents, suggesting an inactivated state block. A fast application of paliperidone during repolarization reversibly inhibited the hERG tail currents in a concentration-dependent manner with a IC value of 1.26 μM. Kinetic analysis of paliperidone interaction with the open state of the hERG channels showed that the rate constants of association (k ) and dissociation (k ) for paliperidone were 0.45 μM s and 1.07 s, respectively. Paliperidone shifted the steady-state inactivation curve of the hERG currents in a hyperpolarizing direction and also produced a use-dependent block. Risperidone and paliperidone had no effect on hERG and hERG 3.1 channel trafficking to the cell membrane. Our results indicated that paliperidone inhibited the hERG current by preferentially interacting with the open and inactivated states of the channel, but not by disruption of hERG channel protein trafficking.
利培酮及其活性代谢物之一帕利哌酮被广泛用于治疗精神分裂症。我们采用膜片钳研究来探究帕利哌酮对在人胚肾（HEK）细胞中表达的人乙醚 - 去极化相关基因（hERG）钾通道的影响。蛋白质免疫印迹分析用于研究利培酮和帕利哌酮对hERG及hERG 3.1亚型通道转运的影响。利培酮和帕利哌酮以浓度依赖性方式抑制hERG尾电流，其半数抑制浓度（IC）值分别为0.16和0.57 μM。帕利哌酮对hERG电流的阻断具有电压依赖性，在通道激活的一系列电压范围内增强。快速施加帕利哌酮可抑制由5秒去极化脉冲至 +60 mV引发的hERG电流，使hERG电流完全失活，提示存在失活状态阻断。在复极化过程中快速施加帕利哌酮以浓度依赖性方式可逆地抑制hERG尾电流，IC值为1.26 μM。对帕利哌酮与hERG通道开放状态相互作用的动力学分析表明，帕利哌酮的结合速率常数（k）和解离速率常数（k）分别为0.45 μM⁻¹ s⁻¹和1.07 s⁻¹。帕利哌酮使hERG电流的稳态失活曲线向超极化方向移动，并且还产生了使用依赖性阻断。利培酮和帕利哌酮对hERG及hERG 3.1通道向细胞膜的转运没有影响。我们的结果表明，帕利哌酮通过优先与通道的开放和失活状态相互作用来抑制hERG电流，而不是通过破坏hERG通道蛋白的转运。
