Mechanism of inhibition by olanzapine of cloned hERG potassium channels. (16th November 2015)

• Record Type: Journal Article
• Authors: Lee, Hong Joon; Choi, Jin-Sung; Hahn, Sang June
• Is Part Of: Neuroscience letters. Volume 609(2015)
• Page Start: 97
• Page End: 102
• Publication Date: 2015-11-16
• Subjects: hERG channel -- Olanzapine -- Open-channel block; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2015.10.039
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Olanzapine is widely used in the treatment of schizophrenia. Olanzapine inhibited hERG in a concentration-dependent manner. Olanzapine interacted with the activated states of the hERG channel. Abstract: Olanzapine is widely used in the treatment of schizophrenia and related psychoses. We investigated the effects of olanzapine on human ether-a-go–go related gene (hERG) channels stably expressed in human embryonic kidney (HEK) cells using the whole-cell patch-clamp technique. Olanzapine inhibited hERG tail currents at −50 mV in a concentration-dependent manner with an IC50 value of 8.0 μM and a Hill coefficient of 0.9. The voltage-dependent inhibition of the hERG currents by olanzapine increased steeply in the voltage range of channel activation. Olanzapine also shifted the steady-state activation curve of the hERG currents in a hyperpolarizing direction. At more depolarized potentials where the channels were fully activated (between 0 and +50 mV), the olanzapine inhibition was voltage-independent. The steady-state inactivation curve of the hERG currents was shifted in the hyperpolarizing direction in the presence of olanzapine. A fast application of olanzapine induced a reversible inhibition of the hERG tail currents during repolarization in a concentration-dependent manner with an IC50 value of 11.9 μM, suggesting an open-channel block. Olanzapine also decreased the hERG current elicited by a 5 s depolarizing pulse to +60 mV to inactivate the hERG currents, suggesting an inhibition of the activated (open and/or inactivated) states of the channels. These results indicated that olanzapine inhibited the hERG current by preferentially interacting with the activated states of the channel.