Effects of Paroxetine on a Human Ether-a-go-go-related Gene (hERG) K⁺ Channel Expressed in Xenopus Oocytes and on Cardiac Action Potential
10.11620/IJOB.2018.43.1.043
- Author:
Hee Kyung HONG
1
;
Soobeen HWANG
;
Su Hyun JO
Author Information
1. Department of Physiology, Kangwon National University Institute of Bioscience & Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine, Chuncheon 200-701, Korea. suhyunjo@kangwon.ac.kr
- Publication Type:Original Article
- Keywords:
hERG channel;
LQT;
Paroxetine;
Rapidly-activating delayed rectifier K⁺ current;
Torsades de pointes
- MeSH:
Action Potentials;
Animals;
Arrhythmias, Cardiac;
Guinea Pigs;
Heart;
Humans;
Long QT Syndrome;
Muscle Cells;
Oocytes;
Paroxetine;
Salivary Glands;
Serotonin;
Tail;
Torsades de Pointes;
Xenopus
- From:International Journal of Oral Biology
2018;43(1):43-51
- CountryRepublic of Korea
- Language:English
-
Abstract:
K⁺ channels are key components of the primary and secondary basolateral Cl- pump systems, which are important for secretion from the salivary glands. 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 a human K⁺ channel, human ether-a-go-go-related gene (hERG), 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 (I(Kr)) in the heart. Mutations in hERG reduce I(Kr) 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. In guinea pig ventricular myocytes held at 36℃, 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 of clinical administration of paroxetine.
