title: Inhibition of cloned hERG potassium channels by risperidone and paliperidone.
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 IC50values 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 IC50value 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-1s-1and 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.
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
authors.forename: Hong Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54097, South Korea.
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea. sjhahn@catholic.ac.kr.
authors.forename: Sang June
authors.identifier: http://orcid.org/0000-0002-6785-1868
authors.initials: SJ
authors.lastname: Hahn
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D000068882:Paliperidone Palmitate / Q000008:administration & dosage / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D018967:Risperidone / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: Open-channel block; Paliperidone; Risperidone; hERG; hERG 3.1 isoform