• The Korean Journal of Physiology and Pharmacology
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• v.6 no.1
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• pp.1-7
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• 2002

Congenital Long QT syndrome (LQTs) is a relatively rare pathologic disorder but results frequently in sudden cardiac death. Of the six LQTs that have been clinically described, five have been worked out for their genetic and biophysical profile. Most are generated by mutations which cause a loss of function in two delayed $K^+$ currents, $i_{Ks}\;and\;i_{Kr}.$ One syndrome is generated by mutations in the $Na^+$ channel which causes essentially a gain of function in the channel. Clinically the syndromes are characterized by slowed repolarization of the cardiac ventricular action potential and the occurrence of typical arrhythmias with undulating peaks in the electrocardiogram, called Torsade de Pointes. Arrhythmias are initiated by early or delayed afterdepolarizations and continue as reentry. Triggers for cardiac events are exercise (swimming; LQT1), emotion (arousal; LQT2) and rest/sleep (LQT3). ${\beta}-blockers$ have a high efficacy in the treatment of LQT1 and LQT2. In LQT3 their use is questionable. The study of congenital LQTsyndromes is a remarkable example of how basic and clinical science converge and take profit of each other's contribution.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.367-371
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• 2001

The chromosome 7-linked long QT syndrome (LQT2) is caused by mutations in the human ether-a- go-go-related gene (HERG) that encodes the rapidly activating delayed rectifier $K^+$ current, $I_{Kr},$ in cardiac myocytes. Different types of mutations have been identified in various locations of HERG channel. One of the mechanisms for the loss of normal channel function is due to membrane trafficking of channel protein. The decreased channel function in some deletion mutants appears to be due to loss of coupling with wild type HERG to form the functional channel as the tetramer. Most of missense mutants with few exceptions could interact with wild type HERG to form functional tetramer and caused dominant negative suppression with co-injection with wild type HERG showing variable effects on current amplitude, voltage dependence, and kinetics of activation and inactivation. Two missense mutants at pore regions of HERG found in Japanese LQT2 (A614V and V630L) showed accentuated inward rectification due to a negative shift in steady-state inactivation and fast inactivation. One mutation in S4 region (R534C) produced a negative shift in current activation, indicating the S4 serving as the voltage sensor and accelerated deactivation. The C-terminus mutation, S818L, could not express the current by mutant alone and did not show dominant negative suppression with co-injection of equal amount of wild type cRNA. Co-injection of excess amount of mutant with wild type produced dominant negative suppression with a shift in voltage dependent activation. Therefore, multiple mechanisms are involved in different mutations and functional abnormality in LQT2. Further characterization with the interactions between various mutants in HERG and the regulatory subunits of the channels (MiRP1 and minK) is to be clarified.

• Biomedical Science Letters
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• v.14 no.2
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• pp.123-126
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• 2008

Long QT Syndrome (LQT) is a congenital disease due to the failure of electrical system of the heart. We have analyzed KCNE1 gene which is known to be the cause of Type V LQT in Korean genome. Although SNPs of KCNE1 have been reported for Chinese and Malaysians no data are available for Korean people yet. PCR primers were prepared to investigate the sequences for normal and SNP at G30A, G112A, C162T. They were different only by 3' ends. Genomic DNAs were extracted from the people who were known to be normal clinically (35) or patients (20) with metabolic disease. As results, we were able to recognize several SNPs in these Korean samples. Some people were homozygous or heterozygous depending upon the type of SNP. This study should facilitate the research on the cause of Type VLQTs and to develop the further therapy at genetic level.

• 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)

• 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)

• 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 Korean Biophysical Society Conference
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• 1997.07a
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• pp.31-31
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• 1997

Rapidly activating delayed K current (IKr) in cardiac muscles plays an important in repolarization. Expression of HERG cloned by the study on inherited LQT revealed that it encodes a potassium channel with biophysical properties similar to those of IKr in cardiac myocytes： outward currents activating on depolarization with large tail currents on repolarization, implying the inward rectifying property.(omitted)

• Biomedical Science Letters
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• v.16 no.4
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• pp.299-305
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• 2010

KCNE1 is the causal gene of long QT syndrome. KCNE1 gene is located in chromosome 21. In compliance with this KCNE1 gene the proteins come out. KCNE1 is responsible for $K^+$ channel which maintains the normal function of the heart muscle for contraction. Affected individuals manifest prolongation of the QT interval on electrocardiongrams, a sign of abnormal cardiac repolarization. The clinical features of LQT result from episodic cardiac arrhythmias, such as torsade de pointes and ventricular fibrllation. Blood DNA was isolated and kept in $4^{\circ}C$ refrigerator. The KCNE1 gene was amplified by PCR method and about 414 bp band was identified by agarose gel electrophoresis. PCR products were inserted into pGEX-4T-1 vector in order to express KCNE1 protein after treatment with IPTG SDS-PAGE was carried out and the protein band which was about 47 kDa was clearly odserved. Results of this study would contribute to the detailed understanding of KCNE1 protein function and to designing better treatment of Long QT symdrome.

• Neonatal Medicine
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• v.28 no.1
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• pp.59-63
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• 2021

An important, albeit rare, cause of fetal bradycardia is long QT syndrome (LQTS). Congenital LQTS is an ion channelopathy caused by mutations in genes encoding cardiac ion channel proteins. Fetal onset of LQTS imposes high risk of life-threatening tachyarrhythmias and sudden cardiac death. Here, we report the case of a female newborn with fetal onset of bradycardia and a 2:1 atrioventricular (AV) block. After birth, a 12-lead electrocardiogram (ECG) revealed bradycardia with QT prolongation of a corrected QT (QTc) interval of 680 ms and pseudo 2:1 AV block. Genetic testing identified a heterozygous Gly402Ser (c.1204G>A) mutation in CACNA1C, confirming the diagnosis of LQTS type 8 (LQT8). The patient received propranolol at a daily dose of 2 mg/kg. Mexiletine was subsequently administered owing to the sustained prolongation of the QT interval and pseudo 2:1 AV block. One week after mexiletine inception, the ECG still showed QT interval prolongation (QTc, 632 ms), but no AV block was observed. There were no life-threatening tachyarrhythmias in a follow-up period of 13 months.

• Archives of Pharmacal Research
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• v.29 no.4
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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.