• The Korean Journal of Physiology and Pharmacology
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• v.21 no.1
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• pp.75-82
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• 2017

The effects of acepromazine on human ether-$\grave{a}$-go-go-related gene (hERG) potassium channels were investigated using whole-cell voltage-clamp technique in human embryonic kidney (HEK293) cells transfected with hERG. The hERG currents were recorded with or without acepromazine, and the steady-state and peak tail currents were analyzed for the evaluating the drug effects. Acepromazine inhibited the hERG currents in a concentration-dependent manner with an $IC_{50}$ value of $1.5{\mu}M$ and Hill coefficient of 1.1. Acepromazine blocked hERG currents in a voltage-dependent manner between -40 and +10 mV. Before and after application of acepromazine, the half activation potentials of hERG currents changed to hyperpolarizing direction. Acepromazine blocked both the steady-state hERG currents by depolarizing pulse and the peak tail currents by repolarizing pulse; however, the extent of blocking by acepromazine in the repolarizing pulse was more profound than that in the depolarizing pulse, indicating that acepromazine has a high affinity for the open state of the channels, with a relatively lower affinity for the closed state of hERG channels. A fast application of acepromazine during the tail currents inhibited the open state of hERG channels in a concentration-dependent. The steady-state inactivation of hERG currents shifted to the hyperpolarized direction by acepromazine. These results suggest that acepromazine inhibits the hERG channels probably by an open- and inactivated-channel blocking mechanism. Regarding to the fact that the hERG channels are the potential target of drug-induced long QT syndrome, our results suggest that acepromazine can possibly induce a cardiac arrhythmia through the inhibition of hERG channels.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.5
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• pp.305-310
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• 2010

The human $ether$-$a$-$go$-$go$-related gene ($hERG$) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the effects of two antipsychotics, tiapride and sulpiride, on hERG channels expressed in $Xenopus$ oocytes and also on delayed rectifier $K^+$ currents in guinea pig cardiomyocytes. Neither the amplitude of the hERG outward currents measured at the end of the voltage pulse, nor the amplitude of hERG tail currents, showed any concentration-dependent changes with either tiapride or sulpiride ($3{\sim}300{\mu}M$). However, our findings did show that tiapride increased the potential for half-maximal activation ($V_{1/2}$) of HERG at $10{\sim}300{\mu}M$, whereas sulpiride increased the maximum conductance ($G_{max}$) at 3, 10 and $100{\mu}M$. In guinea pig ventricular myocytes, bath applications of 100 and $500{\mu}M$ tiapride at $36^{\circ}C$ blocked rapidly activating delayed rectifier $K^+$ current ($I_{Kr}$) by 40.3% and 70.0%, respectively. Also, sulpiride at 100 and $500{\mu}M$ blocked $I_{Kr}$ by 38.9% and 76.5%, respectively. However, neither tiapride nor sulpiride significantly affected the slowly activating delayed rectifier $K^+$ current ($I_{Ks}$) at the same concentrations. Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of IKr are well above the reported therapeutic plasma concentrations of free and total compound.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.3
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• pp.215-220
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• 2009

Chlorpheniramine is a potent first-generation histamine $H_1$ receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The $IC_{50}$ of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the $H_1$ antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.90.3-91
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• 2003

The most commonly proposed mechanism for QT interval prolongation(LQT) by pharmaceuticals is inhibition of the rapid delayed rectifier potassium channel (I$\_$Kr/). The LQT potency of pharmaceuticals can be effectively evaluated by examining the effect on hERG channels expressed in CHO cells, known to be equal to I$\_$Kr/. But, It was known that hERG channels according to increase the bath temperature have several changes, including a marked increase in the amplitude of the outward and tail currents, and acceleration of the rates of activation, recovery from inactivation, and deactivation. (omitted)

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.1
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• pp.37-42
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• 2013

Taxifolin glycoside is a new drug candidate for the treatment of atopic dermatitis (AD). Many drugs cause side effects such as long QT syndrome by blocking the human ether-a-go-go related gene (hERG) $K^+$ channels. To determine whether taxifolin glycoside would block hERG $K^+$ channels, we recorded hERG $K^+$ currents using a whole-cell patch clamp technique. We found that taxifolin glycoside directly blocked hERG $K^+$ current in a concentration-dependent manner ($EC_{50}=9.6{\pm}0.7{\mu}M$). The activation curve of hERG $K^+$ channels was negatively shifted by taxifolin glycoside. In addition, taxifolin glycoside accelerated the activation time constant and reduced the onset of the inactivation time constant. These results suggest that taxifolin glycoside blocks hERG $K^+$ channels that function by facilitating activation and inactivation process.

• International Journal of Oral Biology
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• v.43 no.1
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• pp.43-51
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• 2018

$K^+$ 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.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.77.1-77.1
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• 2003

Prolongation of the QT interval may result in a potentially dangerous arrhythmia. The most commonly proposed mechanism for QT interval prolongation(LQT) by pharmaceuticals is inhibition of the rapid delayed rectifier potassium channel (I$\sub$Kr). The LQT potency of pharmaceuticals can be effectively evaluated by examining the effect on human ether-a go-go-related gene (hERG) channels expressed in CHO cells, known to be equal to I$\sub$kr/. We have transfected JERG into CHO cell lines transiently to express high levels of functional hERG channels. (omitted)

• Molecules and Cells
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• v.37 no.9
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• pp.656-663
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• 2014

Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits $[Ca^{2+}]_i$ transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier $K^+$ ($I_{Ks}$) channel is a cardiac $K^+$ channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating $I_{Ks}$ channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human $I_{Ks}$ channel activity by expressing human $I_{Ks}$ channels in Xenopus oocytes. We found that gintonin enhances $I_{Ks}$ channel currents in concentration- and voltage-dependent manners. The $EC_{50}$ for the $I_{Ks}$ channel was $0.05{\pm}0.01{\mu}g/ml$. Gintonin-mediated activation 1 of the $I_{Ks}$ channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an $IP_3$ receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the $I_{Ks}$ channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 $[Ca^{2+}]_i$/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on $I_{Ks}$ channel. However, gintonin had no effect on hERG $K^+$ channel activity. These results show that gintonin-mediated enhancement of $I_{Ks}$ channel currents is achieved through binding of the $[Ca^{2+}]_i$/CaM complex to the C terminus of KCNQ1 subunit.