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Inhibition of cloned hERG potassium channels by risperidone and paliperidone

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Abstract

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 IC50 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 IC50 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 +1) and dissociation (k −1) for paliperidone were 0.45 μM−1 s−1 and 1.07 s−1, 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.

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Acknowledgements

We thank Professor Jamie Vandenberg (Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia) for the Kv11.1-3.1 plasmid. This work was supported by a grant from the Catholic Medical Center Research Foundation made in the program year of 2016.

Authorship contributions

Participated in research design: BH Choi and SJ Hahn

Conducted experiments: HJ Lee

Performed data analysis and interpretation: HJ Lee, JS Choi

Wrote or contributed to the writing of the manuscript: SJ Hahn

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Authors and Affiliations

  1. Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea

    Hong Joon Lee & Sang June Hahn

  2. College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea

    Jin-Sung Choi

  3. Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54097, South Korea

    Bok Hee Choi

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  1. Hong Joon Lee
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Correspondence to Sang June Hahn.

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Lee, H.J., Choi, JS., Choi, B.H. et al. Inhibition of cloned hERG potassium channels by risperidone and paliperidone. Naunyn-Schmiedeberg's Arch Pharmacol 390, 633–642 (2017). https://doi.org/10.1007/s00210-017-1364-5

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