PDF(Pubmed)
Abstract：
The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (INa) leading to potentially lethal cardiac arrhythmias. NaV1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane and particularly high levels at the intercalated disc region. NaV1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localized at either the lateral membrane or intercalated disc. One of the NaV1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of NaV1.5, we here provide an overview of previously demonstrated interactions between NaV1.5 interacting proteins and +TIPs, which potentially (in)directly impact on NaV1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific NaV1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and NaV1.5 interacting proteins mediates the targeted delivery of NaV1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of NaV1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies.
摘要：
心脏钠通道NaV1.5是心脏兴奋性的重要调节剂，质膜上的NaV1.5水平降低，钠电流（INa）随之降低，导致潜在的致死性心律失常。NaV1.5以特定的模式分布在心肌细胞的质膜上，本地化在顶峰，凹槽,和侧膜的T小管，在插入的椎间盘区域特别高。NaV1.5与相互作用的蛋白质形成大型大分子复合物，并受其调节，其中一些特别位于侧膜或插层椎间盘。NaV1.5贩运路线之一是通过微管（MT），受MT+末端跟踪蛋白（+TIPs）调节。在我们寻找NaV1.5靶向递送的机制时，我们在此概述了先前证明的NaV1.5相互作用蛋白和+TIP之间的相互作用。这可能(在)直接影响NaV1.5贩运。引人注目的是，+TIP与几种嵌入的圆盘和侧膜特异性NaV1.5相互作用蛋白广泛相互作用。最近的工作表明，+TIPs和NaV1.5相互作用蛋白的这种相互作用介导NaV1.5在特定心肌细胞亚细胞结构域的靶向递送，同时也可能与其他离子通道的运输有关。这些观察结果与与NaV1.5丢失相关的疾病特别相关，特别是在侧膜（例如Duchenne型肌营养不良症），或在插层盘(例如，心律失常性心肌病)，并为开发新的抗心律失常疗法开辟了潜在的途径。
