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Veronika Matschke, Ilaria Piccini, Janina Schubert, Eva Wrobel, Florian Lang, Johann Matschke, Elsie Amedonu, Sven Meuth, Timo Strünker, Nathalie Strutz-Seebohm, Boris Greber, Jürgen Scherkenbeck, Guiscard Friedrich Aldous Seebohm

• \(\textit {Background/Aims:}\) 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. \(\textit {Methods:}\) Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in \(\textit {Xenopus laevisoocytes}\) and on iPSC cardiomyocytes overexpressing Kv7.1 channels. \(\textit {Results:}\) We show that currents carried by Kv7.1 (\(EC_{50}\) = 1.48 \(\mu\)M), Kv7.1/KCNE1 (\(EC_{50}\) = 4.9 \(\mu\)M), and Kv7.4 (\(EC_{50}\) = 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 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. \(\textit {Conclusion:}\) Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.