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J Korean Med Sci
2009 Dec 01;246:1089-98. doi: 10.3346/jkms.2009.24.6.1089.
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Inhibition of the human ether-a-go-go-related gene (HERG) K+ channels by Lindera erythrocarpa.
Hong HK
,
Yoon WJ
,
Kim YH
,
Yoo ES
,
Jo SH
.
Abstract
Lindera erythrocarpa Makino (Lauraceae) is used as a traditional medicine for analgesic, antidote, and antibacterial purposes and shows anti-tumor activity. We studied the effects of Lindera erythrocarpa on the human ether-a-go-go-related gene (HERG) channel, which appears of importance in favoring cancer progression in vivo and determining cardiac action potential duration. Application of MeOH extract of Lindera erythrocarpa showed a dose-dependent decrease in the amplitudes of the outward currents measured at the end of the pulse (I(HERG)) and the tail currents of HERG (I(tail)). When the BuOH fraction and H(2)O fraction of Lindera erythrocarpa were added to the perfusate, both I(HERG) and I(tail) were suppressed, while the hexane fraction, CHCl(3) fraction, and EtOAc fraction did not inhibit either I(HERG) or I(tail). The potential required for half-maximal activation caused by EtOAc fraction, BuOH fraction, and H(2)O fraction shifted significantly. The BuOH fraction and H(2)O fraction (100 microg/mL) decreased g(max) by 59.6% and 52.9%, respectively. The H(2)O fraction- and BuOH fraction-induced blockades of I(tail) progressively decreased with increasing depolarization, showing the voltage-dependent block. Our findings suggest that Lindera erythrocarpa, a traditional medicine, blocks HERG channel, which could contribute to its anticancer and cardiac arrhythmogenic effect.
Fig. 1. Effect of Lindera erythrocarpa on human-ether-a-go-go-related-gene (HERG) currents elicited by depolarizing voltage pulses. (A) Superimposed current traces elicited by depolarizing voltage pulses (4 sec) in 10 mV steps (upper panel) from a holding potential of -70 mV in the absence of L. erythrocarpa extract (control, middle panel) and in the presence of 100 µg/mL L. erythrocarpa extract (lower panel). (B) Plot of the HERG current (IHERG) measured at the end of depolarizing pulses against the pulse potential in different concentrations of L. erythrocarpa extract (obtained from A). (C) Plot of the normalized tail current measured at its peak just after repolarization. The amplitude of the tail current in the absence of L. erythrocarpa extract was taken as one. Control data were fitted to the Boltzmann equation, y=1/{1+exp [(-V+V1/2)/dx]}, with V1/2 of -15.2 mV. (D) Activation curves with values normalized to the respective maximum value at each concentration of L. erythrocarpa extract. Symbols with error bars represent means±SEM (n=8).
Fig. 2. Effect of L. erythrocarpa extract on the activated current-voltage relationship. (A) Superimposed current traces elicited by various levels of test pulses ranging from -140 to +50 mV following the pre-pulse to +50 mV for 1.5 sec ("inactivation" voltage-clamp protocol, upper panel) before and after the application of 100 µg/mL L. erythrocarpa extract (center and lower panels, respectively). (B) The I-V curve is for the maximal repolarization-evoked (tail) outward currents against the repolarization potential. Symbols with error bars represent the means±S.E.M. (n=9).
Fig. 3. Effect of different solvent fractions of L. erythrocarpa on the HERG current by comparing the changes of IHERG and tail currents with each solvent fraction: the hexane fraction, CHCl3 fraction, EtOAc fraction, BuOH fraction, and H2O fraction at the same concentrations (100 µg/mL). (A) Superimposed current traces from a cell depolarized to +30 mV before and after exposure to the hexane fraction, CHCl3 fraction, EtOAc fraction, BuOH fraction, and H2O fraction of L. erythrocarpa, respectively. (B) Plot of the HERG current (IHERG) measured at the end of depolarizing pulses against the pulse potential in different solvent fractions of L. erythrocarpa (obtained from A). (C) Plot of the normalized tail current measured at its peak just after repolarization. The amplitude of the tail current in the absence of L. erythrocarpa was taken as one. Control data were fitted to the Boltzmann equation, y=1/{1+exp[(-V+V1/2)/dx]}, with V1/2 of -15.3 mV. (D) Activation curves with values normalized to the respective maximum value for each fraction of L. erythrocarpa. Symbols with error bars represent means±SEM (n=8-22).
Fig. 4. Voltage dependence of HERG current blocked by the H2O fraction of L. erythrocarpa. (A) Current traces from a cell depolarized to -40 mV (left panel), 0 mV (middle panel) and +40 mV (right panel), before and after exposure to 30 µg/mL of the H2O fraction of L. erythrocarpa, showing increased blockade of HERG current at the more negative potential. The protocol consisted of 4-sec depolarizing steps to -40 mV, 0 mV or +40 mV from a holding potential of -70 mV, followed by repolarization to -60 mV. (B) HERG current inhibition at different voltages by the H2O fraction of L. erythrocarpa. At each depolarizing voltage step (-40, -20, 0, +20 or +40 mV), the tail currents in the presence of 30 µg/mL H2O fraction of L. erythrocarpa were normalized to the tail current obtained in the absence of L. erythrocarpa. Bars with error bars represent means±SEM (n=6). (C) Concentration-dependent block of HERG current by the H2O fraction at different membrane potentials. At each depolarizing voltage step (-30 mV, 0 mV or +30 mV), the tail currents in the presence of various concentrations of the H2O fraction were normalized to the tail current obtained in the absence of L. erythrocarpa, and plotted against H2O fraction concentrations. Symbols with error bars represent means±SEM (n=6). The line represents the data fits to the Hill equation.
Fig. 5. Voltage dependence of HERG current blocked by the BuOH fraction of L. erythrocarpa. (A) Current traces from a cell depolarized to -40 mV (left panel), 0 mV (middle panel) and +40 mV (right panel), before and after exposure to 30 µg/mL of the BuOH fraction of L. erythrocarpa, showing an increased blockade of HERG current at the more negative potential. The protocol consisted of 4-sec depolarizing steps to -40 mV, 0 mV or +40 mV from a holding potential of -70 mV, followed by repolarization to -60 mV. (B) HERG current inhibition at different voltages by the BuOH fraction of L. erythrocarpa. At each depolarizing voltage step (-40, -20, 0, +20 or +40 mV), the tail currents in the presence of 30 µg/mL BuOH fraction of L. erythrocarpa were normalized to the tail current obtained in the absence of L. erythrocarpa. Bars with error bars represent means±SEM (n=6). (C) Concentration-dependent block of HERG current by the BuOH fraction at different membrane potentials. At each depolarizing voltage step (-30 mV, 0 mV or +30 mV), the tail currents in the presence of various concentrations of the BuOH fraction were normalized to the tail current obtained in the absence of L. erythrocarpa, and plotted against BuOH fraction concentrations. Symbols with error bars represent means±SEM (n=6). The line represents the data fits to the Hill equation.
Fig. 6. Relative change in sustained HERG currents in response to H2O or BuOH fractions of L. erythrocarpa. (A, C) Original recording of currents under control conditions (Control) and in the presence of H2O (A) or BuOH (C) fraction of L. erythrocarpa (100 µg/mL each) during voltage steps to 0 mV. After having recorded the control measurement, the oocyte was clamped at -70 mV for 13 min during superfusion with the each fraction. (B, D) Relative current (Irel) obtained by dividing the H2O (C) or BuOH (D) fraction current by the control currents of the recording in A or C, respectively. Time 0 ms corresponds to the beginning of the depolarizing voltage step.
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