Int J Oral Biol.  2018 Mar;43(1):43-51. 10.11620/IJOB.2018.43.1.043.

Effects of Paroxetine on a Human Ether-a-go-go-related Gene (hERG) K⁺ Channel Expressed in Xenopus Oocytes and on Cardiac Action Potential

Affiliations
  • 1Department 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

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.

Keyword

hERG channel; LQT; Paroxetine; Rapidly-activating delayed rectifier K⁺ current; Torsades de pointes

MeSH Terms

Action Potentials*
Animals
Arrhythmias, Cardiac
Guinea Pigs
Heart
Humans*
Long QT Syndrome
Muscle Cells
Oocytes*
Paroxetine*
Salivary Glands
Serotonin
Tail
Torsades de Pointes
Xenopus*
Paroxetine
Serotonin
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