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Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, KCa1.1, in Sinus Node Function and Arrhythmia Risk
Circulation: Genomic and Precision Medicine ( IF 6.0 ) Pub Date : 2021-02-25 , DOI: 10.1161/circgen.120.003144
Santiago Pineda 1 , Vesna Nikolova-Krstevski 2, 3 , Christiana Leimena 2 , Andrew J Atkinson 4 , Ann-Kristin Altekoester 2 , Charles D Cox 2 , Arie Jacoby 2 , Inken G Huttner 2, 3 , Yue-Kun Ju 5 , Magdalena Soka 2 , Monique Ohanian 2 , Gunjan Trivedi 2 , Sreehari Kalvakuri 1 , Katja Birker 1 , Renee Johnson 2, 3 , Peter Molenaar 6, 7 , Dennis Kuchar 8 , David G Allen 5 , Dirk F van Helden 9 , Richard P Harvey 2, 3 , Adam P Hill 2, 3 , Rolf Bodmer 1 , Georg Vogler 1 , Halina Dobrzynski 4, 10 , Karen Ocorr 1 , Diane Fatkin 2, 3, 8
Affiliation  

Background:KCNMA1 encodes the α-subunit of the large-conductance Ca2+-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 1 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.

中文翻译:

大电导钙激活钾通道 KCa1.1 在窦房结功能和心律失常风险中的保守作用

背景:KCNMA1编码大电导 Ca 2+激活的 K +通道的 α 亚基K Ca 1.1,并且位于心房颤动 (AF) 的连锁区间内。对 K Ca 1.1心脏功能的了解有限,KCNMA1尚未作为 AF 候选基因进行研究。方法:对118 名家族性 AF 患者进行了KCNMA1基因测序。在人类、小鼠、斑马鱼和苍蝇中评估了 K Ca 1.1 在正常心脏结构和功能中的作用。一个新的KCNMA1变体在功能上被表征。结果:一个复杂的KCNMA1在 1 个与 AF 的亲属中鉴定出变异。为了评估潜在的疾病机制,我们首先使用免疫染色和免疫金电子显微镜评估了 K Ca 1.1 在正常心脏中的分布。K Ca 1.1 可见于人和小鼠的整个心房和心室,在窦房结中强烈表达。在离体小鼠窦房结制备中,添加 K Ca 1.1 拮抗剂帕西林,可减缓肾上腺素能受体刺激引起的搏动率增加。在斑马鱼胚胎中敲除 K Ca 1.1 直向同源物kcnma1b导致窦性心动过缓伴扩张和心房和心室收缩减少。果蝇的遗传失活K Ca 1.1 ortholog,slo,全身或在成人阶段,也减慢心跳并产生纤颤性心脏收缩。缓慢缺陷果蝇的电生理特征显示动作电位的爆发,反映了纤维性心律失常事件的增加。具有人类KCNMA1突变体心脏特异性过表达的果蝇也表现出心脏周期增加和动作电位爆发,类似于 K Ca 1.1 功能丧失模型。结论:我们的数据表明 K Ca 1.1 在人类、小鼠、斑马鱼和苍蝇的窦房结功能,并表明 K Ca 1.1 功能丧失可能易患 AF。
更新日期:2021-04-20
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