title: The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.
authors.affiliation: Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Matschke
authors.forename: Ilaria
authors.initials: I
authors.lastname: Piccini
authors.forename: Janina
authors.initials: J
authors.lastname: Schubert
authors.forename: Eva
authors.initials: E
authors.lastname: Wrobel
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Johann
authors.initials: J
authors.lastname: Matschke
authors.forename: Elsie
authors.initials: E
authors.lastname: Amedonu
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Timo
authors.initials: T
authors.lastname: Strünker
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.forename: Boris
authors.initials: B
authors.lastname: Greber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scherkenbeck
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects*; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072417:Protein Domains; D055503:Protein Multimerization / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D001688:Biological Products; D051657:KCNQ1 Potassium Channel; C085746:rottlerin