Mechanism of inhibition by olanzapine of cloned hERG potassium channels.
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 -50mV in a concentration-dependent manner with an IC50 value of 8.0μM 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 +50mV), 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 11.9μM, suggesting an open-channel block. Olanzapine also decreased the hERG current elicited by a 5s depolarizing pulse to +60mV 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.
Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Hong Joon
HJ
Lee
College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, Gyeonggi-do, South Korea.
Jin-Sung
JS
Choi
Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea. Electronic address: sjhahn@catholic.ac.kr.
Sang June
SJ
Hahn
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D000077152:Olanzapine; D018408:Patch-Clamp Techniques
D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D001569:Benzodiazepines; D000077152:Olanzapine
Olanzapine; Open-channel block; hERG channel