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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents



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ID: 732123.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels
Authors:Matschke, V.; Piccini, I.; Schubert, J.; Wrobel, E.; Lang, F.; Matschke, J.; Amedonu, E.; Meuth, S. G.; Strunker, T.; Strutz-Seebohm, N.; Greber, B.; Scherkenbeck, J.; Seebohm, G.
Date of Publication (YYYY-MM-DD):2016
Title of Journal:Cell Physiol Biochem
Volume:40
Issue / Number:6
Start Page:1549
End Page:1558
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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 muM), Kv7.1/KCNE1 (EC50 = 4.9 muM), and Kv7.4 (EC50 = 0.148 muM) 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.
Free Keywords: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
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
Identifiers:ISSN:1421-9778 (Electronic) 1015-8987 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/27997884 [ID No:2]
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