Orange flavonoid hesperetin modulates cardiac hERG potassium channel via binding to amino acid F656 |
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Authors: | Scholz Eberhard P Zitron Edgar Kiesecker Claudia Thomas Dierk Kathöfer Sven Kreuzer Jörg Bauer Alexander Katus Hugo A Remppis Andrew Karle Christoph A Greten Johannes |
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Institution: | aDepartment of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany;bSt. Vincenz Hospital, Limburg, Germany;cGerman Society of Traditional Chinese Medicine, Heidelberg, Germany |
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Abstract: | Background and aimsHesperetin belongs to the flavonoid subgroup classified as citrus flavonoids and is the main flavonoid in oranges. A high dietary intake of flavonoids has been associated with a significant reduction in cardiovascular mortality. HERG potassium channels play a major role in cardiac repolarisation and represent the most important pharmacologic target of both antiarrhythmic and proarrhythmic drugs.Methods and resultsWe used the two-microelectrode voltage-clamp technique to analyse inhibitory effects of hesperetin on hERG potassium channels heterologously expressed in Xenopus oocytes. Hesperetin blocked hERG potassium channels in a concentration dependent manner. Onset of block was fast and completely reversible upon wash-out. There was no significant effect of hesperetin on channel kinetics. Affinity of hesperetin to mutant F656A hERG channel was significantly decreased compared to WT hERG, indicating a binding site in the channel pore cavity. In contrast, affinity of hesperetin to Y652A hERG was not different from the affinity to WT hERG.ConclusionWe found an antagonist of cardiac hERG channels that modulates hERG currents by accessing the aromatic pore binding site, particularly amino acid phe-656. Regarding high hesperetin concentrations found in oranges and the increasing consumption of oranges and orange juice in Europe, potential effects of hesperetin on cardiac electrophysiology in vivo deserve further investigation. |
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Keywords: | Flavonoids Hesperetin hERG Potassium channel Arrhythmia Repolarisation |
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