title: Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis.
abstract: The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p<0.001), marked increase in atrial diameter (p<0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Soka
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Alex Horby
authors.initials: AH
authors.lastname: Christensen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Anders P
authors.initials: AP
authors.lastname: Larsen
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Knop
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Nielsen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Andersen
authors.affiliation: Molecular Genetics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Humphreys
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Mann
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Inken G
authors.initials: IG
authors.lastname: Huttner
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Preiss
authors.affiliation: Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Germany.
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark. Electronic address: nschmitt@sund.ku.dk.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology; D016466:CHO Cells; D003412:Cricetulus; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006325:Heart Atria / Q000033:anatomy & histology / Q000503:physiopathology; D006801:Humans; D023421:Models, Animal; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3
keywords: AF; APD; Atrial action potential duration; Atrial fibrillation; BCL; CHO; Chinese hamster ovary; ERP; HRV; K(2)(P); SNP; TASK-1; Two-pore domain potassium channels; WT; action potential duration; atrial fibrillation; basic cycle length; effective refractory period; heart rate variability; hours post fertilization; hpf; single nucleotide polymorphisms; two-pore domain K(+) channels; wild-type