Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc.
Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc.
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DOI：
10.1038/ncomms10342
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发表时间：
2016-01-20
影响因子：
16.6
通讯作者：
Delmar M
中科院分区：
文献类型：
--
作者：
Leo-Macias A;Agullo-Pascual E;Sanchez-Alonso JL;Keegan S;Lin X;Arcos T;Feng-Xia-Liang;Korchev YE;Gorelik J;Fenyö D;Rothenberg E;Rothenberg E;Delmar M
细胞间粘附和电兴奋性被认为是独立的细胞特性。然而，对有髓纤维的研究表明，电压门控钠通道（VGSC）与细胞粘附分子在离散的亚细胞位置聚集，如朗维尔结。心肌中类似大分子组织的证据缺失。在这里，我们结合联合收割机纳米成像（单分子定位显微镜，电子显微镜，和“角度"扫描膜片钳）与数学模拟，以证明不同的枢纽在心脏闰盘，集群的粘附分子N-钙粘蛋白和VGSC NaV1.5。我们表明，N-钙粘蛋白-NaV1.5协会不是随机的，NaV1.5分子在这些集群是心脏钠电流的主要贡献者，和NaV1.5表达的损失降低细胞间粘附强度。我们推测，粘附/兴奋性节点的收缩和电分子装置的串扰的关键网站，并可能代表心肌病的VGSC复合物的分子突变的患者的结构基板。 在有髓纤维中，传导和粘附蛋白聚集在离散的病灶处，但尚不清楚这种组织是否存在于其他可兴奋细胞中。使用纳米可视化和计算机技术，作者表明，粘附/兴奋性节点存在于成人心肌的闰盘。
Intercellular adhesion and electrical excitability are considered separate cellular properties. Studies of myelinated fibres, however, show that voltage-gated sodium channels (VGSCs) aggregate with cell adhesion molecules at discrete subcellular locations, such as the nodes of Ranvier. Demonstration of similar macromolecular organization in cardiac muscle is missing. Here we combine nanoscale-imaging (single-molecule localization microscopy; electron microscopy; and ‘angle view' scanning patch clamp) with mathematical simulations to demonstrate distinct hubs at the cardiac intercalated disc, populated by clusters of the adhesion molecule N-cadherin and the VGSC NaV1.5. We show that the N-cadherin-NaV1.5 association is not random, that NaV1.5 molecules in these clusters are major contributors to cardiac sodium current, and that loss of NaV1.5 expression reduces intercellular adhesion strength. We speculate that adhesion/excitability nodes are key sites for crosstalk of the contractile and electrical molecular apparatus and may represent the structural substrate of cardiomyopathies in patients with mutations in molecules of the VGSC complex. In myelinated fibres conduction and adhesion proteins aggregate at discrete foci, but it is unclear if this organization is present in other excitable cells. Using nanoscale visualization and in silico techniques, the authors show that adhesion/excitability nodes exist at the intercalated discs of adult cardiac muscle.