Referenced in: none

Automatically associated channels: Kv11.1

Title: Mechanism of inhibition by olanzapine of cloned hERG potassium channels.

Authors: Hong Joon Lee, Jin-Sung Choi, Sang June Hahn

Journal, date & volume: Neurosci. Lett., 2015 Nov 16 , 609, 97-102

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26484507

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 -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.