Korean J Physiol Pharmacol.  2013 Feb;17(1):37-42. 10.4196/kjpp.2013.17.1.37.

Taxifolin Glycoside Blocks Human ether-a-go-go Related Gene K+ Channels

• Yun J
• Bae H
• Choi SE
• Kim JH
• Choi YW
• Lim I
• Lee CS
• Lee MW
• Ko JH
• Seo SJ
• Bang H

• KMID: 1432761
• DOI: http://doi.org/10.4196/kjpp.2013.17.1.37

Abstract

Taxifolin glycoside is a new drug candidate for the treatment of atopic dermatitis (AD). Many drugs cause side effects such as long QT syndrome by blocking the human ether-a-go-go related gene (hERG) K+ channels. To determine whether taxifolin glycoside would block hERG K+ channels, we recorded hERG K+ currents using a whole-cell patch clamp technique. We found that taxifolin glycoside directly blocked hERG K+ current in a concentration-dependent manner (EC50=9.6+/-0.7 microM). The activation curve of hERG K+ channels was negatively shifted by taxifolin glycoside. In addition, taxifolin glycoside accelerated the activation time constant and reduced the onset of the inactivation time constant. These results suggest that taxifolin glycoside blocks hERG K+ channels that function by facilitating activation and inactivation process.

Keyword

hERG K+ channel; Long QT syndrome; Patch clamp; Taxifolin glycoside

MeSH Terms

Dermatitis, Atopic
Humans
Long QT Syndrome
Quercetin
Quercetin

Figure

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  Fig. 1 Effects of taxifolin glycoside on hERG K+ currents. (A) Representative hERG K+ current traces in control and 30µM taxifolin glycoside-treated sample were recorded using a two-stage voltage protocol (upper panel). (B) Normalized I-V relationships for current measured at the peak of repolarizing tail current (Itail) in the absence and the presence of 30 µM taxifolin glycoside. (C) Concentration-response relationships for taxifolin glycoside in Itail. Data were fitted with the Hill equation and EC50 was 9.6±0.7µM (n=5).

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  Fig. 2 Effects of taxifolin glycoside on activation kinetics of the hERG K+ channels. (A) Activation time constants in the absence and the presence of 30 µM taxifolin glycoside. Time constant obtained from a single exponential fit the deporlazing step current (Istep, Fig. 1A) (n=5, *p<0.05). (B) Voltage-dependent activation curves in the absence and the presence of 30 µM taxifolin glycoside, as calculated from the normalized peak tail current amplitudes (n=5, *p<0.05). Smooth curve were fitted with the Boltzmann function.

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  Fig. 3 Effects of taxifolin glycoside on the steady-state inactivation of the hERG K+ channels. (A) Representative current traces for the steady-state inactivation in control and 30 µM taxifolin glycoside treated sample. (B) Normalized steady-state inactivation curves before and after exposure to 30 µM taxifolin glycoside. Smooth curves were fitted with the Boltzmann function (n=5). (C) The time constants of steady-state inactivation. The time constants obtained from a single exponential fit the decay of the outward current (n=5).

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  Fig. 4 Effects of taxifolin glycoside on the onset of inactivation of hERG K+ channels. (A) Representative current traces for the onset of inactivation in control and 30 µM taxifolin glycoside-treated sample. (B) The time constant for the onset of inactivation were measured by fitting a single exponential function to the decaying current (n=5, *p<0.05).

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  Fig. 5 Effect of taxifolin glycoside on the recovery from inactivation of hERG K+ channels. (A) Representative current traces for the recovery from inactivation in control and 30 µM taxifolin glycoside-treated sample. (B) The time constant for the recovery from inactivation were obtained by fitting a single exponential function to the initial increase in tail current amplitude (n=5).

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