• 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.

• Archives of Pharmacal Research
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• 제29권10호
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• pp.834-839
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• 2006

Torilin was purified from Torilis japonica (Houtt.) DC., and its effects on a rapidly activating delayed rectifier $K^+$ channel (hKv1.5), cloned from human heart and stably expressed in Ltk cells, as well as the corresponding $K^+$ current (the ultrarapid delayed rectifier, $I_{KUR}$) were assessed in human atrial myocytes. Using the whole cell configuration of the patch-clamp technique, torilin was found to inhibit the hKv1.5 current in time and voltage-dependent manners, with an $IC_50$ value of $2.51{\pm}0.34\;{\mu}M$ at +60 mV. Torilin accelerated the inactivation kinetics of the hKv1.5 channel, and slowed the deactivation kinetics of the hKv1.5 current, resulting in a tail crossover phenomenon. Additionally, torilin inhibited the hKv1.5 current in a use dependent manner. These results strongly suggest that torilin is a type of open-channel blocker of the hKv1.5 channel.

• BMB Reports
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• 제43권11호
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• pp.756-760
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• 2010

Recent studies have reported that delayed-rectifier Kv channels regulate apoptosis in the nervous system. Herein, we investigated changes in the expression of the delayed-rectifier Kv channels Kv1.2, Kv2.1, and Kv3.1 after acute spinal cord injury (SCI) in rats. We performed RT-PCR analysis and found an increase in the level of Kv2.1 mRNA after SCI but no significant changes in the levels of Kv1.2 and Kv3.1 mRNA. Western blot analysis revealed that Kv2.1 protein levels rapidly decreased and then dramatically increased from 1 day, whereas Kv3.1b protein levels gradually and sharply decreased at 5 days. Kv1.2 protein levels did not change significantly. In addition, Kv2.1 clusters were disrupted in the plasma membranes of motor neurons after SCI. Interestingly, the expressional changes and translocation of Kv2.1 were consistent with the apoptotic changes on day 1. Therefore, these results suggest that Kv2.1 channels probably contribute to neuronal cell responses to SCI.

• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 1996년도 정기총회 및 학술발표회
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• pp.5-5
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• 1996

In sino-atrial node cells which act as the normal pacemaker of the heart, K conductance in resting state is minimal due to the absence of inward rectifier K channels K conductance only increases when the membrane is depolarized by the activation of the delayed rectifier K current I$\_$k/. In the present study, we investigated the gating mechanism of$\_$k/ using the whole cell patch clamp technique in isolated single sinoatrial cells of the rabbit. (omitted)

• Journal of Ginseng Research
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• 제37권3호
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• pp.324-331
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• 2013

Channels formed by the co-assembly of the KCNQ1 subunit and the mink (KCNE1) subunit underline the slowly activating delayed rectifier $K^+$ channels ($I_{Ks}$) in the heart. This $K^+$ channel is one of the main pharmacological targets for the development of drugs against cardiovascular disease. Panax ginseng has been shown to exhibit beneficial cardiovascular effects. In a previous study, we showed that ginsenoside Rg3 activates human KCNQ1 $K^+$ channel currents through interactions with the K318 and V319 residues. However, little is known about the effects of ginsenoside metabolites on KCNQ1 $K^+$ alone or the KCNQ1 + KCNE1 $K^+$ ($I_{Ks}$) channels. In the present study, we examined the effect of protopanaxatriol (PPT) and compound K (CK) on KCNQ1 $K^+$ and $I_{Ks}$ channel activity expressed in Xenopus oocytes. PPT more strongly inhibited the $I_{Ks}$ channel currents than the currents of KCNQ1 $K^+$ alone in concentration- and voltage-dependent manners. The $IC_{50}$ values on $I_{Ks}$ and KCNQ1 alone currents for PPT were $5.18{\pm}0.13$ and $10.04{\pm}0.17{\mu}M$, respectively. PPT caused a leftward shift in the activation curve of $I_{Ks}$ channel activity, but minimally affected KCNQ1 alone. CK exhibited slight inhibition on $I_{Ks}$ and KCNQ1 alone $K^+$ channel currents. These results indicate that ginsenoside metabolites show limited effects on $I_{Ks}$ channel activity, depending on the structure of the ginsenoside metabolites.

• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 1999년도 학술발표회 진행표 및 논문초록
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• pp.22-23
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• 1999

Voltage-gated $K^{＋}$ channels represent the most complex group of ion channel genes expressed in cardiovascular system. The human Kv1.5 channel (hKv1.5) represents the $I_{Kur}$ repolarizing current in atrial myocytes. The hKv1.5 channel is functionally modulated by the Kv$\beta$1.3 subunit, which converts it from a delayed rectifier to a channel with rapid inactivation and enhanced voltage sensitivity.(omitted)d)

• The Korean Journal of Physiology and Pharmacology
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• 제5권1호
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• pp.33-40
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• 2001

The aim of present study was to define the cellular mechanisms underlying changes in delayed rectifier $K^+\;(K_{DR})$ channel function in isoproterenol-induced hypertrophy. It has been proposed that $K_{DR}$ channels play a role in regulation of vascular tone by limiting membrane depolarization in arterial smooth muscle cells. The alterations of the properties of coronary $K_{DR}$ channels have not been studied as a possible mechanism for impaired coronary reserve in cardiac hypertrophy. The present study was carried out to compare the properties of coronary $K_{DR}$ channels in normal and hypertrophied hearts. These channels were measured from rabbit coronary smooth muscle cells using a patch clamp technique. The main findings of the study are as follows: (1) the $K_{DR}$ current density was decreased without changes of the channel kinetics in isoproterenol-induced hypertrophy; (2) the sensitivity of coronary $K_{DR}$ channels to 4-AP was increased in isoproterenol-induced hypertrophy. From the above results, we suggest for the first time that the alteration of $K_{DR}$ channels may limit vasodilating responses to several stimuli and may be involved in impaired coronary reserve in isoproterenol-induced hypertrophy.

• 생명과학회지
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• 제19권10호
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• pp.1484-1488
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• 2009

가족성 저칼륨성 주기성 마비란 상염색체 우성 유전 질환으로 저칼륨혈증을 동반한 간헐적인 가역적 이완성 근육 마비를 특징으로 한다. 세포내 저류된 칼륨으로 인해 저칼륨혈증이 지속되고 근세포 활성이상으로 인해 마비가 발생하는 것으로 알려져 있다. 이러한 증상발현의 분자생물학적 기전을 확인하기 위해 세포 내 칼륨이온을 세포 밖으로 이동시키는 지연성 정류형 채널 단백질의 일종인 KCNQ3와 KCNQ5를 대상으로, 정상인과 환자에서 채취한 골격근 세포를 생리적 세포외 정상 칼륨농도인 4 mM과 탈분극 유도를 위한 고칼륨농도인 50mM에 노출시켜 단백질의 양적 변화 유무를 확인하였다. 유전자 발현양상을 확인하기 위해 mRNA의 양적 변화를 확인한 결과 모든 조건에서 유의한 변화가 관찰되지 않아 정상 칼륨조건과 고칼륨조건이 두 유전자발현의 변화를 야기하지 않음을 확인하였다. 그러나 단백질 양을 관찰한 결과 환자의 골격근 세포가 50 mM의 칼륨농도에 노출되는 경우 KCNQ3 단백질은 세포질 내에서 증가하고 세포막 내에서 감소하였다. 이는 환자의 골격근 세포가 고농도의 세포외 칼륨에 의해 탈분극 되는 경우 재분극에 중요한 기능을 담당하는 KCNQ3 채널 단백질이 세포질 내로 이동하여 재분극 형성의 장애를 초래하고 이로 인해 근세포 활성이 일어나지 않게 되어 마비를 유발할 수 있음을 시사하는 결과로 본 질환의 새로운 발병 기전을 설명할 수 있는 근거로 생각된다.

• The Korean Journal of Physiology and Pharmacology
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• 제5권5호
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• pp.413-421
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• 2001

An impaired smooth muscle cell (SMC) relaxation of coronary artery by alteration of $K^+$ channels would be the most potential explanation for reduced coronary reserve in left ventricular hypertrophy (LVH), however, this possibility has not been investigated. We performed morphometrical analysis of the coronary artery under electron microscopy and measured $Ca^{2+}-activated\;K\;(K_{Ca})$ currents and delayed rectifier K $(K_{dr})$ currents by whole-cell and inside-out patch-clamp technique in single coronary arterial SMCs from rabbits subjected to isoprenaline-induced cardiac hypertrophy. Coronary arterial SMCs underwent significant changes in ultrastructure. The unitary current amplitude and the open-state probability of $K_{Ca}$ channel were significantly reduced in hypertrophy without open-time and closed-time kinetic. The concentration-response curve of $K_{Ca}$ channel to $Ca^{2+}$ is shifted to the right in hypertrophy. The reduction in the mean single channel current and increase in the open channel noise of $K_{Ca}$ channel by TEA were more sensitive in hypertrophy. $K_{dr}$ current density is significantly reduced in hypertrophy without activation and inactivation kinetics. The sensitivity of $K_{dr}$ current on 4-AP is significantly increased in hypertrophy. This is the first study to report evidence for alterations of $K_{Ca}$ channels and $K_{dr}$ channels in coronary SMCs with LVH. The findings may provide some insight into mechanism of the reduced coronary reserve in LVH.

• 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.