The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels.

Abstract

BACKGROUND/AIMS:

Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases.

METHODS:

Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels.

RESULTS:

We show that currents carried by Kv7.1 (EC50 = 1.48 μM), Kv7.1/KCNE1 (EC50 = 4.9 μM), and Kv7.4 (EC50 = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.

CONCLUSION:

Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.

• Authors: Veronika Matschke, Ilaria Piccini, Janina Schubert, Eva Wrobel, Florian Lang, Johann Matschke, Elsie Amedonu, Sven G Meuth, Timo Strünker, Nathalie Strutz-Seebohm, Boris Greber, Jürgen Scherkenbeck, Guiscard Seebohm
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 40 Issue 6 Pg. 1549-1558 ( 2016) ISSN: 1421-9778 [Electronic] Germany
• PMID: 27997884 (Publication Type: Journal Article)
• Copyright: © 2016 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• Acetophenones
• Benzopyrans
• Biological Products
• KCNQ1 Potassium Channel
• rottlerin

Topics

• Acetophenones (chemistry, pharmacology)
• Animals
• Benzopyrans (chemistry, pharmacology)
• Biological Products (chemistry, pharmacology)
• Computer Simulation
• Humans
• Induced Pluripotent Stem Cells (cytology)
• Ion Channel Gating (drug effects)
• KCNQ1 Potassium Channel (chemistry, metabolism)
• Membrane Potentials (drug effects)
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Protein Domains
• Protein Multimerization (drug effects)
• Xenopus laevis