title: Inhibition of Cardiac Kir Current (IK1) by Protein Kinase C Critically Depends on PKCβ and Kir2.2.
abstract: BACKGROUND
  Cardiac inwardly rectifying Kir current (IK1) mediates terminal repolarisation and is critical for the stabilization of the diastolic membrane potential. Its predominant molecular basis in mammalian ventricle is heterotetrameric assembly of Kir2.1 and Kir2.2 channel subunits. It has been shown that PKC inhibition of IK1 promotes focal ventricular ectopy. However, the underlying molecular mechanism has not been fully elucidated to date.
  
  
  RESULTS
  In the Xenopus oocyte expression system, we observed a pronounced PKC-induced inhibition of Kir2.2 but not Kir2.1 currents. The PKC regulation of Kir2.2 could be reproduced by an activator of conventional PKC isoforms and antagonized by pharmacological inhibition of PKCβ. In isolated ventricular cardiomyocytes (rat, mouse), pharmacological activation of conventional PKC isoforms induced a pronounced inhibition of IK1. The PKC effect in rat ventricular cardiomyocytes was markedly attenuated following co-application of a small molecule inhibitor of PKCβ. Underlining the critical role of PKCβ, the PKC-induced inhibition of IK1 was absent in homozygous PKCβ knockout-mice. After heterologous expression of Kir2.1-Kir2.2 concatemers in Xenopus oocytes, heteromeric Kir2.1/Kir2.2 currents were also inhibited following activation of PKC.
  
  
  CONCLUSIONS
  We conclude that inhibition of cardiac IK1 by PKC critically depends on the PKCβ isoform and Kir2.2 subunits. This regulation represents a potential novel target for the antiarrhythmic therapy of focal ventricular arrhythmias.
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherer
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Xynogalos
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Andrassy
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D014982:Xenopus laevis
chemical_list: C489461:Kir2.1 channel; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C