Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, 43210, USA.
Circulation. 2011 Sep 13;124(11):1212-22. doi: 10.1161/CIRCULATIONAHA.111.023986. Epub 2011 Aug 22.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone. Despite decades of research, surprisingly little is known regarding the molecular pathways underlying the pathogenesis of AF. ANK2 encodes ankyrin-B, a multifunctional adapter molecule implicated in membrane targeting of ion channels, transporters, and signaling molecules in excitable cells.
In the present study, we report early-onset AF in patients harboring loss-of-function mutations in ANK2. In mice, we show that ankyrin-B deficiency results in atrial electrophysiological dysfunction and increased susceptibility to AF. Moreover, ankyrin-B(+/-) atrial myocytes display shortened action potentials, consistent with human AF. Ankyrin-B is expressed in atrial myocytes, and we demonstrate its requirement for the membrane targeting and function of a subgroup of voltage-gated Ca(2+) channels (Ca(v)1.3) responsible for low voltage-activated L-type Ca(2+) current. Ankyrin-B is associated directly with Ca(v)1.3, and this interaction is regulated by a short, highly conserved motif specific to Ca(v)1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Ca(v)1.3 expression, membrane localization, and function sufficient to produce shortened atrial action potentials and arrhythmias. Finally, we demonstrate reduced ankyrin-B expression in atrial samples of patients with documented AF, further supporting an association between ankyrin-B and AF.
These findings support that reduced ankyrin-B expression or mutations in ANK2 are associated with AF. Additionally, our data demonstrate a novel pathway for ankyrin-B-dependent regulation of Ca(v)1.3 channel membrane targeting and regulation in atrial myocytes.
心房颤动（AF）是最常见的心律失常，仅在美国就影响超过 200 万名患者。尽管经过几十年的研究，但对于 AF 发病机制的分子途径，人们的了解仍然少之又少。ANK2 编码锚蛋白-B，这是一种多功能衔接分子，参与可兴奋细胞中离子通道、转运蛋白和信号分子的膜靶向。
在本研究中，我们报告了携带 ANK2 功能丧失突变的患者中早发性 AF。在小鼠中，我们表明锚蛋白-B 缺乏会导致心房电生理功能障碍和 AF 易感性增加。此外，ankyrin-B(+/-)心房肌细胞显示动作电位缩短，与人类 AF 一致。锚蛋白-B 在心房肌细胞中表达，我们证明它是膜靶向和功能的电压门控 Ca(2+)通道（Ca(v)1.3）的亚群所必需的，该亚群负责低电压激活的 L 型 Ca(2+)电流。ankyrin-B 与 Ca(v)1.3 直接相关，这种相互作用受 Ca(v)1.3 特有的短而高度保守的基序调节。此外，心房肌细胞中锚蛋白-B 的缺失导致 Ca(v)1.3 的表达、膜定位和功能减少，足以产生缩短的心房动作电位和心律失常。最后，我们证明了在有记录 AF 的患者的心房样本中，ankyrin-B 的表达减少，进一步支持了 ankyrin-B 与 AF 之间的关联。
这些发现支持 ankyrin-B 表达减少或 ANK2 突变与 AF 相关。此外，我们的数据表明了 ankyrin-B 依赖性调节 Ca(v)1.3 通道膜靶向和心房肌细胞调节的新途径。
