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J Ginseng Res
2011 Jun 01;352:191-9. doi: 10.5142/jgr.2011.35.2.191.
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Differential effects of ginsenoside metabolites on HERG k channel currents.
Choi SH
,
Shin TJ
,
Hwang SH
,
Lee BH
,
Kang J
,
Kim HJ
,
Oh JW
,
Bae CS
,
Lee SH
,
Nah SY
.
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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 Rg3 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 α subunits in Xenopus oocytes. CK induced a large persistent deactivating-tail current (Ideactivating-tail ) and significantly decelerated deactivating current decay in a concentration-dependent manner. The EC50 for persistent Ideactivating-tail was 16.6±1.3 μM. In contrast to CK, PPT accelerated deactivating-tail current deactivation. PPD itself had no effects on deactivating-tail currents, whereas PPD inhibited ginsenoside Rg3-induced persistent Ideactivating-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.
Fig. 1. Chemical structures of ginsenoside Rg3 and ginsenoside metabolites used in this study. CK, compound K; PPD, protopanaxadiol; PPT, protopanaxatriol; Glc, glucopyranoside.
Fig. 2. Effects of compound K (CK) on IHERG, Itail, and Ideactivating-tail. (A) Representative current traces on human ether-a-go-go-related gene (HERG) K+ channel enhancements by various concentrations of CK. Currents were in response to 4-s voltage steps to 0 mV from a holding potential of â90 mV, followed by repolarization to â60 mV. IHERG was obtained at the end of depolarization; Itail was obtained at beginning of repolarization; slow Ideactivating-tail was obtained at the end of repolarization as indicated by arrow in (A). (B) Concentration-response curves for the activation of HERG K+ currents by CK on IHERG, Itail, and Ideactivating-tail. Solid lines were fitted to the Hill equation. CK was potent for the enhancement of Ideactivating-tail. Bars represent the means±SEM (n=5-7). (C) The representative control (upper traces) and 100 μM CK-mediated currents (down traces) in I-V relationship. Currents were recorded at test potential from â60 to + 50 mV. Itail and Ideactivating-tail were recorded after repolarization to â60 mV. (D) I-V relationships for HERG K+ currents measurement at the end of the 4-s test pulse before and after application of 3, 10, and 30 μM CK (n=5). Currents were normalized to the control current at 0 mV for each oocyte. Data are represented by the means±SEM (n=7). (E) Effects of CK on the steady-state activation curve for HERG K+ channel. Itail were normalized to the peak current under each condition, and the data were fitted with a Boltzmann function. Treatment of CK (10, 30, and 100 μM) did cause a leftward shift. Con, control.
Fig. 3. Effects of protopanaxatriol (PPT) on IHERG, Itail, and Ideactivating-tail. (A) Representative current traces on human ether-a-go-go-related gene (HERG) K+ channel inhibitions by various concentrations of PPT. Currents were in response to 4-s voltage steps to 0 mV from a holding potential of â90 mV, followed by repolarization to â60 mV. IHERG was obtained at the end of depolarization; Itail was obtained at beginning of repolarization; slow Ideactivating-tail was obtained at the end of repolarization as indicated by the arrow. (B) Concentration-response curves for the inhibition of HERG K+ currents by PPT on IHERG, Itail, and Ideactivating-tail. Solid lines were fitted to the Hill equation. PPT was potent for the inhibition of Ideactivating-tail. Bars represent the means±SEM (n=5-7). (C) The representative control (upper traces) and 100 μM PPT-mediated currents (down traces) in I-V relationship. Currents were recorded at test potential from â60 to +50 mV. Itail and Ideactivating-tail were recorded after repolarization to â60 mV. (D) I-V relationships for HERG K+ currents measurement at the end of the 4-s test pulse before and after application of 3, 10, and 30 μM PPT (n=5). Currents were normalized to the control current at 0 mV for each oocyte. Data are represented by the means±SEM (n=7). (E) Effects of PPT on the steady-state activation curve for HERG K+ channel. Itail were normalized to the peak current under each condition, and the data were fitted with a Boltzmann function. Treatment of PPT (3, 10, and 30 μM) did not cause a leftward shift. Con, control.
Fig. 4. Effects of protopanaxadiol (PPD) on Rg3-mediated IHERG, Itail, and Ideactivating-tail. (A) Representative current traces on human ether-a-go-go-related gene (HERG) K+ channel inhibitions by various concentrations of PPD itself (left panel). Currents were in response to 4-s voltage steps to 0 mV from a holding potential of â90 mV, followed by repolarization to â60 mV. IHERG was obtained at the end of depolarization; Itail was obtained at beginning of repolarization; slow Ideactivating-tail was obtained at the end of repolarization as indicated by the arrow. Concentration-dependent inhibitions of HERG K+ currents by PPD on Rg3-mediated IHERG, Itail, and Ideactivating-tail (right panel). (B) I-V relationships for HERG K+ currents measurement at the end of the 4-s test pulse before (upper traces) and after application of 1 μM Rg3 plus 100 μM PPD (down traces). Currents were normalized to the control current at 0 mV for each oocyte (right panel). Data are represented by the means±SEM (n=7). (C) Concentration-response curves for the activation of HERG K+ currents by Rg3 in the absence or presence of PPD on IHERG, Itail, and Ideactivating-tail. Solid lines were fitted to the Hill equation. PPD significantly affected Ideactivating-tail. Bars represent the means±SEM (n=5-7). (D) Effects of PPD on Rg3-mediated the steady-state activation curve for HERG K+ channel. Itail were normalized to the peak current under each condition, and the data were fitted with a Boltzmann function. Treatment of 100 μM PPD in the presence of 0.3, 1, or 3 μM Rg3 did not cause a leftward shift. Con, control.
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