Key result
KCa1.1 channel loss-of-function drives bradycardia and arrhythmias in animals, linking KCNMA1 variants to AF.
Why the study?
Insights into cardiac functions of KCa1.1 are limited, and KCNMA1, which lies within a linkage interval for AF, had not been investigated as an AF candidate gene.
The KCa1.1 channel plays a highly conserved role in sinus node function across species, and its loss of function may predispose to atrial fibrillation.
Background KCNMA1 encodes the α-subunit of the large-conductance Ca 2+ -activated K + channel, K Ca 1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K Ca 1.1 are limited and KCNMA1 has not been investigated as an AF candidate gene. Methods and Results KCNMA1 sequencing in 118 patients with familial AF identified a novel complex variant in one kindred. To evaluate potential disease mechanisms, we first evaluated the distribution of K Ca 1.1 in normal hearts using immunostaining and immunogold electron microscopy. K Ca 1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K Ca 1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K Ca 1.1 ortholog, kcnma1b , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila K Ca 1.1 ortholog, slo , systemically or in adult stages, also slowed the heartbeat and produced cardiac arrhythmias. Electrophysiological characterization of slo- deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the K Ca 1.1 loss-of-function models. Conclusions Our data point to a highly conserved role of K Ca 1.1 in sinus node function in humans, mice, zebrafish and fly and suggest that K Ca 1.1 loss of function may predispose to AF.
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Pineda et al. (2020) studied Familial atrial fibrillation (n=118). KCa1.1 loss-of-function and KCNMA1 mutation models vs. Wild-type/normal models was evaluated on Sinus node function and arrhythmia development. Loss-of-function of the KCa1.1 channel in animal models caused sinus bradycardia and fibrillatory arrhythmias, suggesting KCNMA1 variants may predispose to atrial fibrillation.
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