Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K <sub>Ca</sub> 1.1, in Sinus Node Function and Arrhythmia Risk
Santiago Pineda, Vesna Nikolova-Krstevski, Christiana Leimena, Andrew Atkinson, Ann-Kristin Alteköester, Charles D. Cox, Arie S. Jacoby, Inken G. Huttner, Yue‐Kun Ju, Magdalena Soka, Monique Ohanian, Gunjan Trivedi, Sreehari Kalvakuri, Katja Birker, Renée Johnson, Peter Molenaar, Dennis L. Kuchar, David G. Allen, Dirk van Helden, Richard P. Harvey, Adam P. Hill, Rolf Bodmer, Georg Vogler, Halina Dobrzynski, Karen Ocorr, Diane Fatkin
Abstract
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: The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of K Ca 1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized. Results: A complex KCNMA1 variant was identified in 1 kindred with AF. 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 fibrillatory cardiac contractions. 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.