Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K Ca 1.1, in Sinus Node Function and Arrhythmia Risk

Pineda, Santiago and Nikolova-Krstevski, Vesna and Leimena, Christiana and Atkinson, Andrew J. and Altekoester, Ann-Kristin and Cox, Charles D. and Jacoby, Arie and Huttner, Inken G. and Ju, Yue-Kun and Soka, Magdalena and Ohanian, Monique and Trivedi, Gunjan and Kalvakuri, Sreehari and Birker, Katja and Johnson, Renee and Molenaar, Peter and Kuchar, Dennis and Allen, David G. and van Helden, Dirk F. and Harvey, Richard P. and Hill, Adam P. and Bodmer, Rolf and Vogler, Georg and Dobrzynski, Halina and Ocorr, Karen and Fatkin, Diane (2021) Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K Ca 1.1, in Sinus Node Function and Arrhythmia Risk. Circulation: Genomic and Precision Medicine, 14 (2). ISSN 2574-8300

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Background - KCNMA1 encodes the alpha-subunit of the large-conductance Ca(2+)-activated K(+) channel, KCa1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of KCa1.1 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 KCa1.1 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 one kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of KCa1.1 in normal hearts using immunostaining and immunogold electron microscopy. KCa1.1 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 KCa1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the KCa1.1 ortholog, kcnma1b, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila KCa1.1 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 KCa1.1 loss-of-function models. Conclusions - Our data point to a highly conserved role of KCa1.1 in sinus node function in humans, mice, zebrafish and fly and suggest that KCa1.1 loss of function may predispose to AF.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 31 Jul 2021 05:36
Last Modified: 31 Jul 2021 05:36

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