• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 1999년도 학술발표회 진행표 및 논문초록
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• pp.64-64
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• 1999

Amitriptyline has been known to induce QT prolongation and ventricular arrhythmias such as torsades de pointes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes.(omitted)

• International Journal of Oral Biology
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• 제43권1호
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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.

• Archives of Pharmacal Research
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• 제29권4호
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• pp.310-317
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• 2006

We investigated the effects of trinitrobenzene sulfonic acid (TNBS), an amino-group reagent, on the human ether-a-go-go-related gene (HERG) $K^+$ channels expressed in Xenopus oocytes. TNBS neutralizes the positively charged amino-groups of peptide N-terminal and lysine residues. External application of TNBS at 10 mM for 5 min irreversibly shifted the curves for currents at the end of the pulse and tail currents of HERG to a more negative potential and decreased the maximal amplitude of the $I_{tail}$ curve $(I_{tail,max})$. TNBS had little effect on either the activated current-voltage relationship or the reversal potential of HERG current, indicating that TNBS did not change ion selectivity properties. TNBS shifted the time constant curves of both activation and deactivation of the HERG current to a more hyperpolarized potential; TNBS's effect was greater on channel opening than channel closing. External $H^+$ is known to inhibit HERG current by shifting $V_{1/2}$ to the right and decreasing $I_{tail,max}$. TNBS enhanced the blockade of external $H^+$ by exaggerating the effect of $H^+$ on $I_{tail,max}$, not on $V_{1/2}$. Our data provide evidence for the presence of essential amino-groups that are associated with the normal functioning of the HERG channel and evidence that these groups modify the blocking effect of external $H^+$ on the current.

• Journal of Ginseng Research
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• 제35권2호
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• pp.191-199
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• 2011

The human ether-a-go-go-related gene (HERG) cardiac $K^+$ channels are one of the representative pharmacological targets for development of drugs against cardiovascular diseases such as arrhythmia. Panax ginseng has been known to exhibit cardioprotective effects. In a previous report we demonstrated that ginsenoside $Rg_3$ regulates HERG $K^+$ channels by decelerating deactivation. However, little is known about how ginsenoside metabolites regulate HERG $K^+$ channel activity. In the present study, we examined the effects of ginsenoside metabolites such as compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT) on HERG $K^+$ channel activity by expressing human a subunits in Xenopus oocytes. CK induced a large persistent deactivatingtail current ($I_{deactivating-tail}$) and significantly decelerated deactivating current decay in a concentration-dependent manner. The $EC_{50}$ for persistent $I_{deactivating-tail}$ was $16.6{\pm}1.3$ ${\mu}M$. In contrast to CK, PPT accelerated deactivating-tail current deactivation. PPD itself had no effects on deactivating-tail currents, whereas PPD inhibited ginsenoside $Rg_3$-induced persistent $I_{deactivating-tail}$ and accelerated HERG $K^+$ channel deactivation in a concentration-dependent manner. These results indicate that ginsenoside metabolites exhibit differential regulation on Ideactivating-tail of HERG $K^+$ channel.

• The Korean Journal of Physiology and Pharmacology
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• 제17권1호
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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.

• 분석과학
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• 제24권6호
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• pp.533-543
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• 2011

hERG (human ether-a-go-go related gene) 이온채널은 심장 재분극의 중요 요소이며 이 채널의 저해제는 부정맥과 돌연사를 유발할 수 있다. 따라서, 신약개발과정에서 후보물질이 hERG 이온채널의 잠재적인 저해제일 경우에는 심장독성 부작용을 유발하므로, 이를 최소화하고자 많은 노력이 집중되고 있다. 본 연구는 HEK(인간 배아 신장)세포에서 얻은 202개 유기화합물의 $IC_{50}$ 데이터를 이용하여 2차원 구조-활성의 정량적 관계(2D-QSAR)방법으로 예측하는 모델을 개발하였다. hERG이온채널 저해제의 기계 학습방법으로는 다중선형회귀(Multiple Linear Regression), 서포트 벡터 머신(Support Vector Machine: SVM)방법과 인공신경망(Artificial Neural Network)방법이며, 교차검증을 적용한 모집단 기반 전진선택(forward selection)방법과 결합하여 각 학습모델에 적합한 최적의 표현자들을 결정하였다. 가장 우수한 방법은 14종의 표현자를 사용한 인공신경망방법($R^2_{CV}$=0.617, RMSECV=0.762, MAECV=0.583)이었고, 다중선형회귀방법을 통해서 hERG이온채널 저해물질의 구조적 특징과 수용체와의 상호작용을 설명할 수 있다. QSAR모델의 검증은 교차검증과 Y-scrambling test방법으로 수행하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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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.

• The Korean Journal of Physiology and Pharmacology
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• 제15권5호
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• pp.291-297
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• 2011

The effect of cyclosporin A (CsA), an immunosuppressant, on human ether-a-go-go-related gene (HERG) channel as it is expressed in human embryonic kidney cells was studied using a whole-cell, patch-clamp technique. CsA inhibited the HERG channel in a concentration-dependent manner, with an $IC_{50}$ value and a Hill coefficient of $3.17{\mu}m$ and 0.89, respectively. Pretreatment with cypermethrine, a calcineurin inhibitor, had no effect on the CsA-induced inhibition of the HERG channel. The CsA-induced inhibition of HERG channels was voltage-dependent, with a steep increase over the voltage range of the channel opening. However, the inhibition exhibited voltage independence over the voltage range of fully activated channels. CsA blocked the HERG channels predominantly in the open and inactivated states rather than in the closed state. Results of the present study suggest that CsA acts directly on the HERG channel as an open-channel blocker, and it acts independently of its effect on calcineurin activity.

• Biomolecules & Therapeutics
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• 제18권4호
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• pp.448-453
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• 2010

Drug-induced long QT syndrome is known to be associated with the onset of torsades de pointes (TdP), resulting in a fatal ventricular arrhythmia. QT interval prolongation can result from blocking the human ether-a-go-go-related gene (hERG) channel, which is important for the repolarization of cardiac action potential. Nicardipine, a Ca-channel blocker and antihypertensive agent, has been reported to increase the risk of occasional serious ventricular arrhythmias. We studied the effects of nicardipine on hERG $K^+$ channels expressed in HEK293 cells and Xenopus oocytes. The cardiac electrophysiological effect of nicardipine was also investigated in this study. Our results revealed that nicardipine dose-dependently decreased the tail current of the hERG channel expressed in HEK293 cells with an $IC_{50}$ of 0.43 ${\mu}M$. On the other hand, nicardipine did not affect hERG channel trafficking. Taken together, nicardipine inhibits the hERG channel by the mechanism of short-term channel blocking. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that nicardipine blocks the hERG channel at the pore of the channel.

• The Korean Journal of Physiology and Pharmacology
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• 제14권5호
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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.