title: Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria.
abstract: OBJECTIVE
  Small-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a functional role in human atria.
  
  
  RESULTS
  Quantitative real-time PCR analyses showed higher transcript levels of SK2 and SK3 than that of the SK1 subtype in human atrial tissue. SK2 and SK3 were reduced in chronic atrial fibrillation (AF) compared with sinus rhythm (SR) patients. Immunohistochemistry using confocal microscopy revealed widespread expression of SK2 in atrial myocytes. Two SK channel inhibitors (NS8593 and ICAGEN) were tested in heterologous expression systems revealing ICAGEN as being highly selective for SK channels, while NS8593 showed less selectivity for these channels. In isolated atrial myocytes from SR patients, both inhibitors decreased inwardly rectifying K(+) currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue.
  
  
  CONCLUSIONS
  SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down-regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Skibsbye
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Poulet
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark Acesion Pharma ApS, Ole Maaløes Vej 3, Copenhagen DK-2200, Denmark.
authors.forename: Jonas Goldin
authors.initials: JG
authors.lastname: Diness
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark Acesion Pharma ApS, Ole Maaløes Vej 3, Copenhagen DK-2200, Denmark.
authors.forename: Bo Hjorth
authors.initials: BH
authors.lastname: Bentzen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden, Medical Faculty, Dresden University of Technology, Dresden, Germany.
authors.forename: Utz
authors.initials: U
authors.lastname: Kappert
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden, Medical Faculty, Dresden University of Technology, Dresden, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.affiliation: Acesion Pharma ApS, Ole Maaløes Vej 3, Copenhagen DK-2200, Denmark mgr@acesionpharma.com.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; C000597600:N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine; D011725:Pyridines; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013844:Thiazoles; D015057:1-Naphthylamine
keywords: Antiarrhythmic drug therapy; Atrial fibrillation; Atrial-specific SK channel; Human heart; Small-conductance calcium-activated potassium channel