Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes
Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes
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DOI：
10.1073/pnas.0403711101
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发表时间：
2004-12-14
影响因子：
11.1
通讯作者：
Bennett, V
中科院分区：
文献类型：
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作者：
Mohler, PJ;Rivolta, I;Bennett, V
我们在Na(v)1.5的锚蛋白结合基元中发现了一个人类突变（E1053K），该突变与Brugada综合征有关，Brugada综合征是一种由Na(v)1.5功能改变引起的致命心律失常。E1053K突变消除了Na(v)1.5与锚蛋白g的结合，也阻止了Nav的积累(1)。5在心室心肌细胞的细胞表面。锚定蛋白g和Na(v)1.5都定位于心肌细胞的嵌入盘膜和t小管膜，Na(v)1.5与大鼠心脏洗涤剂溶出物中的190 kda锚定蛋白g共免疫沉淀。这些数据表明Na(v)1.5与锚蛋白g相关，锚蛋白g是Na(v)1.5在心肌细胞可兴奋膜定位所必需的。结合之前在神经元中的研究，这些在心肌细胞中的结果表明，锚定蛋白g参与了多种可兴奋细胞类型功能位点电压门控Na-v通道定位的共同途径。
We identify a human mutation (E1053K) in the ankyrin-binding motif of Na(v)1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na(v)1.5. The E1053K mutation abolishes binding of Na(v)1.5 to ankyrin-G, and also prevents accumulation of Nav(1).5 at cell surface sites in ventricular cardiomyocytes. Ankyrin-G and Na(v)1.5 are both localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes. Together with previous work in neurons, these results in cardiomyocytes suggest that ankyrin-G participates in a common pathway for localization of voltage-gated Na-v channels at sites of function in multiple excitable cell types.