Abstract
2-pore potassium channel K2P3.1 (TASK-1) modulates background conductance in human atrial cells and could be a drug target for atrial fibrillation (AF). The effects of TASK-1 inactivation on atrial structure and function have not been demonstrated in vivo. Genetic variation in KCNK3, which encodes TASK-1, which might be a determinant of susceptibility to AF is also unknown. Liang et al (J Mol Cell Cardiol 2013, PMID 24374141) evaluated the effects of knockdown of the cardiac zebrafish kcnk3a and kcnk3b genes. Combined kcnk3a and kcnk3b knockdown in embryos resulted in lower heart rate and increase in atrial diameter and end-diastolic ventricular diameter as compared with controls. Screening of KCNK3 in 2 independent AF cohorts (373 participants) identified 3 novel KCNK3 variants. Two present in 1 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, reduced RP and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the TASK-1 pore and loss-of-function. Cardiac AP modeling predicted that reduced TASK prolongs atrial APD. Thus, TASK in the atrium and its inactivation have diverse effects on atrial size and electrophysiological properties that can contribute to AF substrate.
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