Human ETHER-A-Go-Go-Related Gene (HERG) K+ Channel Inhibition by the Antidepressant Paroxetine

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on human ether-a-go-go-related gene (hERG) channels expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier K+ channel (Ikr) in the heart. Mutations in hERG reduce Ikr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias. Paroxetine induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltage-independent during each voltage pulse. The S6 domain mutation Y652A did not affect the drug-induced hERG current block. In guinea-pig ventricular myocytes held at 36°C, treatment with 0.4 μM paroxetine for 5 min decreased the action potential duration at 90% of repolarization (APD90) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of paroxetine.