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Escitalopram block of hERG potassium channels

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Abstract

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.

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Acknowledgments

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2012R1A1A2008274) and by the Research Fund 2012 of The Catholic University of Korea (J.S. Choi).

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Authors and Affiliations

  1. 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

    Yun Ju Chae & Sang June Hahn

  2. Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Korea

    Ji Hyun Jeon & In-Beom Kim

  3. Department of Pharmacology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Korea

    Hong Joon Lee & Ki-Wug Sung

  4. College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, Korea

    Jin-Sung Choi

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  1. Yun Ju Chae
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Correspondence to Sang June Hahn.

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Chae, Y.J., Jeon, J.H., Lee, H.J. et al. Escitalopram block of hERG potassium channels. Naunyn-Schmiedeberg's Arch Pharmacol 387, 23–32 (2014). https://doi.org/10.1007/s00210-013-0911-y

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  • DOI: https://doi.org/10.1007/s00210-013-0911-y

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