title: Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells.
abstract: The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca(2+) in melanocytes. Homozygous Dct knockout (Dct(-/-)) adult mice are vulnerable to atrial arrhythmias (AA).
  
  
  
  The purpose of this study was to determine whether apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) currents are upregulated in Dct(-/-) mice and contribute to AA.
  
  
  
  Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct(-/-) (n = 9) and Dct(+/-) (n = 9) mice.
  
  
  
  Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4-24.1 ms) in Dct(-/-) mice and by 11.5 ms (95% CI 5.4-17.6 ms) in Dct(+/-) mice at a pacing cycle length of 150 ms (P = .047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34-62 ms) for Dct(-/-) mice and 21 ms (95% CI 12-29 ms) for Dct(+/-) mice (P = .002) at baseline, and it was 35 ms (95% CI 21-49 ms) for Dct(-/-) mice and 22 ms (95% CI 11-32 ms) for Dct(+/-) mice (P = .025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9-14.0 ms) in Dct(-/-) mice and by 1.5 ms (95% CI 0.7-2.3 ms) in Dct(+/-) mice (P = .005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct(-/-) mice. AA inducibility (89% vs 11%; P = .003) and duration (281 seconds vs 66 seconds; P = .008) were greater in Dct(-/-) mice than in Dct(+/-) mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct(-/-) mice had focal drivers.
  
  
  
  Apamin-sensitive SK current upregulation in Dct(-/-) mice plays an important role in the mechanism of AA.
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Chan
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California.
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Hsueh
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Everett
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Eue-Keun
authors.initials: EK
authors.lastname: Choi
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Olaopa
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan.
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine and the Fairbanks School of Public Health, Indianapolis, Indiana.
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine and the Fairbanks School of Public Health, Indianapolis, Indiana.
authors.forename: Maria Aleksandra
authors.initials: MA
authors.lastname: Kudela
authors.affiliation: Department of Pediatrics, Riley Heart Research Center, Indianapolis, Indiana.
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart-von der Lohe
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Section of Clinical Cardiac Electrophysiology, Philadelphia, Pennsylvania.
authors.forename: Pooja
authors.initials: P
authors.lastname: Jadiya
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Dhanendra
authors.initials: D
authors.lastname: Tomar
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Section of Clinical Cardiac Electrophysiology, Philadelphia, Pennsylvania.
authors.forename: Emily
authors.initials: E
authors.lastname: Luvison
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Section of Clinical Cardiac Electrophysiology, Philadelphia, Pennsylvania.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Anzalone
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Section of Clinical Cardiac Electrophysiology, Philadelphia, Pennsylvania,; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Vickas V
authors.initials: VV
authors.lastname: Patel
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: chenpp@iu.edu.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008543:Melanins / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D013223:Statistics as Topic; D015854:Up-Regulation; D056969:Voltage-Sensitive Dye Imaging / Q000379:methods
chemical_list: D008543:Melanins; D051640:Small-Conductance Calcium-Activated Potassium Channels; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase
keywords: Apamin; Atrial fibrillation; Melanocyte-like cells; Optical mapping; SK channels