Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 40, Issue 6, Pages 1549-1558Publisher
KARGER
DOI: 10.1159/000453205
Keywords
KCNQ; Activator; Mallotoxin; K channel opener; Cardiac; Heart; iPSC
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Funding
- Deutsche Forschungsgemeinschaft [DFG-Se1077/3-3, DFG INST 2105/27-1]
- IMF Muenster
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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 mu M), Kv7.1/KCNE1 (EC50 = 4.9 mu M), and Kv7.4 (EC50 = 0.148 mu M) 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 slap 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. (C) 2016 The Author(s) Published by S. Karger AG, Basel
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