• 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.

• Journal of Ginseng Research
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• v.37 no.3
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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.

• 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.