title: Block of hERG K+ channel and prolongation of action potential duration by fluphenazine at submicromolar concentration.
abstract: Fluphenazine is a potent antipsychotic drug that can increase action potential duration and induce QT prolongation in several animal models and in humans. As the block of cardiac human ether-a-go-go-related gene (hERG) channels is one of the leading causes of acquired long QT syndrome, we investigated the acute effects of fluphenazine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. Fluphenazine at concentrations of 0.1-1.0 μM increased the action potential duration at 90% of repolarization (APD90) and action potential duration at 50% of repolarization (APD50) in 5 min when action potentials were elicited under current-clamp conditions in guinea pig ventricular myocytes. We examined the effects of fluphenazine on hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. The IC50 for the fluphenazine-induced block of hERG currents in HEK293 cells at 36 °C was 0.102 μM at +20 mV. Fluphenazine-induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The fluphenazine-dependent hERG block in Xenopus oocytes increased progressively relative to the degree of depolarization. Fluphenazine affected the channels in the activated and inactivated states but not in the closed states, and the S6 domain mutation from tyrosine to alanine at amino acid 652 (Y652A) attenuated the hERG current block. These results suggest that the antipsychotic drug fluphenazine is a potent blocker of hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.
authors: Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors: Hee-Kyung
authors: HK
authors: Hong
authors: Byung Hoon
authors: BH
authors: Lee
authors: Mi-Hyeong
authors: MH
authors: Park
authors: Seung Ho
authors: SH
authors: Lee
authors: Daehyun
authors: D
authors: Chu
authors: Woo Jin
authors: WJ
authors: Kim
authors: Han
authors: H
authors: Choe
authors: Bok
authors: B
authors: Hee Choi
authors: Su-Hyun
authors: SH
authors: Jo
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D005476:Fluphenazine / Q000008:administration & dosage*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D014982:Xenopus laevis
chemical_list: D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D005476:Fluphenazine