International Journal of Oral Biology

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

  • Hong, Hee-Kyung (Department of Physiology, Kangwon National University Institute of Bioscience & Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine) ;
  • Hwang, Soobeen (Department of Physiology, Kangwon National University Institute of Bioscience & Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine) ;
  • Jo, Su-Hyun (Department of Physiology, Kangwon National University Institute of Bioscience & Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine)
  • Received : 2018.03.13
  • Accepted : 2018.03.19
  • Published : 2018.03.31
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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 $36^{\circ}C$, treatment with $0.4{\mu}M$ paroxetine for 5 min decreased the action potential duration at 90% of repolarization ($APD_{90}$) 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.

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References

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