Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis

Liang, Bo; Soka, Magdalena; Christensen, Alex Hørby; Olesen, Morten; Larsen, Allan; Knop, Filip K.; Wang, Fan; Nielsen, Jonas B.; Andersen, Martin N.; Humphreys, David T.; Mann, Stefan A.; Huttner, Inken G.; Vandenberg, Jamie I.; Svendsen, Jesper Hastrup; Haunsø, Stig; Preiß, Thomas; Seebohm, Guiscard; Olesen, Søren-Peter; Schmitt, Nicole; Fatkin, Diane

doi:10.1016/j.yjmcc.2013.12.014

Cited by 67 publications

(49 citation statements)

References 29 publications

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“…Transient knockdown of K 2P 3.1 expression affected atrial size in a zebrafish model. Furthermore, reduced K 2P 3.1 current prolonged atrial action potential duration in cardiac action potential modeling, which was potentiated by reciprocal changes in activity of other ion channel currents (247).…”

Section: Cardiac Potassium Channels and Arrhythmiamentioning

confidence: 96%

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Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

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185

184

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About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.

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Section: Cardiac Potassium Channels and Arrhythmiamentioning

confidence: 96%

“…Very recently, impaired K 2P 3.1 function was postulated as an arrhythmogenic substrate (247). Transient knockdown of K 2P 3.1 expression affected atrial size in a zebrafish model.…”

Section: Cardiac Potassium Channels and Arrhythmiamentioning

confidence: 99%

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

Self Cite

185

184

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“…An inactivating mutation in the human TASK-3 channel pore (G236R) is associated with the BirkBarel syndrome of mental retardation, hypotonia, and facial dysmorphism (Barel et al, 2008). Inactivating mutations in human TASK-1 (G203D, G97R, V221L, E182K, T8K, Y192C) are associated with familial pulmonary arterial hypertension (Ma et al, 2013) and atrial arrhythmias (V123L) (Liang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

et al. 2015

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Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2ʹ9-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K 2P ) potassium channel function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118-128 and 228-248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 potassium channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; channel function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC 50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 function by binding at a common site within the channel intracellular pore region, although binding outside the channel pore cannot yet be excluded.

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“…In cardiomyocytes, expression of several K 2P channels was described, with TREK-1 (KCNK2) and TASK-1 as the most detailed studied cardiac leak channels [3][4][5][6][7][8]. Nevertheless, the distinct role of the different K 2P channels in human cardiac pathophysiology and arrhythmogenesis is known only in part so far [9,10]. Recently, we have identified the first K 2P channel mutation that is associated with a cardiac arrhythmia.…”

Section: Introductionmentioning

confidence: 99%