Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation.
Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation.
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DOI：
10.1161/circulationaha.111.023986
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发表时间：
2011-09-13
期刊：
影响因子：
37.8
通讯作者：
Mohler PJ
中科院分区：
文献类型：
--
作者：
Cunha SR;Hund TJ;Hashemi S;Voigt N;Li N;Wright P;Koval O;Li J;Gudmundsson H;Gumina RJ;Karck M;Schott JJ;Probst V;Le Marec H;Anderson ME;Dobrev D;Wehrens XH;Mohler PJ
心房颤动（AF）是最常见的心律失常，仅在美国就有200多万患者。尽管经过数十年的研究，令人惊讶的是，人们对AF发病机制的分子途径知之甚少。ANK2编码锚蛋白b，这是一种涉及可兴奋细胞中离子通道、转运蛋白和信号分子的膜靶向的多功能适配器分子。在这里，我们报道了ANK2功能缺失突变的早发性房颤患者。在小鼠中，我们发现锚蛋白b缺乏导致心房电生理功能障碍和对房颤的易感性增加。此外，锚蛋白b +/ -心房肌细胞表现出缩短的动作电位，与人类房颤一致。锚蛋白b在心房肌细胞中表达，我们证明了它对负责低压激活的l型Ca2+电流的电压门控Ca2+通道亚群（Cav1.3）的膜靶向和功能的要求。锚蛋白b直接与Cav1.3结合，这种相互作用是由Cav1.3特有的一个短的、高度保守的基序调节的。此外，心房肌细胞中锚蛋白b的缺失导致Cav1.3表达减少，膜定位和功能下降，足以产生心房动作电位缩短和心律失常。最后，我们证实了房颤患者心房样本中锚蛋白b表达降低，进一步支持了锚蛋白b与房颤之间的关联。这些发现支持了锚蛋白b表达降低或ANK2突变与房颤相关。此外，我们的数据证明了心房肌细胞中Cav1.3通道膜靶向和调控的锚蛋白b依赖性调控的新途径。
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over two million patients in the US 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. Here, 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 Ca2+ channels (Cav1.3) responsible for low-voltage activated L-type Ca2+current. Ankyrin-B directly associates with Cav1.3, and this interaction is regulated by a short, highly-conserved motif specific to Cav1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Cav1.3 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 atrial fibrillation. Additionally, our data demonstrate a novel pathway for ankyrin-B-dependent regulation of Cav1.3 channel membrane targeting and regulation in atrial myocytes.