Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54097, South Korea.
Eur J Pharmacol. 2019 Jul 5;854:92-100. doi: 10.1016/j.ejphar.2019.04.006. Epub 2019 Apr 5.
Cariprazine is a novel atypical antipsychotic drug that is widely used for the treatment of schizophrenia and bipolar mania/mixed disorder. We used the whole-cell patch-clamp technique to investigate the effects of cariprazine on hERG channels that are stably expressed in HEK cells. Cariprazine inhibited the hERG 1A and hERG 1A/3.1 tail currents at -50 mV in a concentration-dependent manner with IC values of 4.1 and 12.2 μM, respectively. The block of hERG 1A currents by cariprazine was voltage-dependent, and increased over a range of voltage for channel activation. Cariprazine shifted the steady-state inactivation curve of the hERG 1A currents in a hyperpolarizing direction and produced a use-dependent block. A fast application of cariprazine inhibited the hERG 1A currents elicited by a 5 s depolarizing pulse to +60 mV to fully inactivate the hERG 1A currents. During a repolarizing pulse wherein the hERG 1A current was deactivated slowly, cariprazine rapidly and reversibly blocked the open state of the hERG 1A current. However, cariprazine did not affect hERG 1A and hERG 1A/3.1 channel trafficking to the cell membrane. Our results indicated that cariprazine concentration-dependently inhibited hERG 1A and hERG 1A/3.1 currents by preferentially interacting with the open states of the hERG 1A channel, but not by the disruption of hERG 1A and hERG 1A/3.1 channel protein trafficking. Our study examined cariprazine's mechanism of action provides a biophysical profile that is necessary to assess the potential therapeutic effects of this drug.
卡利拉嗪是一种新型非典型抗精神病药物，广泛用于治疗精神分裂症和双相躁狂/混合障碍。我们使用全细胞膜片钳技术研究了卡利拉嗪对稳定表达于 HEK 细胞的 hERG 通道的影响。卡利拉嗪以浓度依赖的方式抑制 -50 mV 时的 hERG 1A 和 hERG 1A/3.1 尾电流，IC 值分别为 4.1 和 12.2 μM。卡利拉嗪对 hERG 1A 电流的阻断具有电压依赖性，并随通道激活的电压范围而增加。卡利拉嗪使 hERG 1A 电流的稳态失活曲线向超极化方向偏移，并产生使用依赖性阻断。快速给予卡利拉嗪可抑制 +60 mV 去极化脉冲诱发的 hERG 1A 电流，使 hERG 1A 电流完全失活。在 hERG 1A 电流缓慢去激活的复极化脉冲中，卡利拉嗪快速且可逆地阻断 hERG 1A 电流的开放状态。然而，卡利拉嗪不影响 hERG 1A 和 hERG 1A/3.1 通道向细胞膜的转运。我们的结果表明，卡利拉嗪通过优先与 hERG 1A 通道的开放状态相互作用，浓度依赖性地抑制 hERG 1A 和 hERG 1A/3.1 电流，而不是通过破坏 hERG 1A 和 hERG 1A/3.1 通道蛋白的转运。我们的研究检验了卡利拉嗪的作用机制，提供了评估该药物潜在治疗效果所需的生物物理特征。
