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KMID : 0848120180430010043
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International Journal of Oral Biology
2018 Volume.43 No. 1 p.43 ~ p.51
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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
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Hong Hee-Kyung
Hwang Soo-Been
Jo Su-Hyun
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Abstract
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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 (IKr) in the heart. Mutations in hERG reduce IKr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to lifethreatening arrhythmias. Paroxetine induced concentrationdependent 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 voltageindependent during each voltage pulse. 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 of clinical administration of paroxetine.
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KEYWORD
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hERG channel, LQT, Paroxetine, Rapidlyactivating delayed rectifier K+ current, torsades de pointes
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