EH Domain Proteins Regulate Cardiac Membrane Protein Targeting
EH Domain Proteins Regulate Cardiac Membrane Protein Targeting
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DOI：
10.1161/circresaha.110.216713
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发表时间：
2010-07-09
影响因子：
20.1
通讯作者：
Mohler, Peter J.
中科院分区：
文献类型：
--
作者：
Gudmundsson, Hjalti;Hund, Thomas J.;Mohler, Peter J.
原理：心肌膜兴奋性由膜相关离子通道、转运体、受体和信号分子组成的集成网络严格调控。健康和疾病中的膜蛋白动力学由一系列复杂的细胞内靶向、支架、循环和降解途径维持。令人惊讶的是，尽管几十年的研究将膜蛋白转运功能障碍与人类心血管疾病联系在一起，但对于这些可兴奋心肌细胞内靶向通路的分子身份或功能基本上一无所知。目的：我们试图发现在原代心肌细胞中膜蛋白靶向的新途径。方法和结果：我们报道了人类心脏膜蛋白转运蛋白大家族的初步特征。我们对新的锚蛋白相关运输蛋白进行了组织范围的筛选，并确定了一个独特的Eps15同源(EH)结构域蛋白家族(EHD1、EHD2、EHD3、EHD4)的4个成员，它们在其他细胞类型的基于内体的膜蛋白靶向中发挥关键作用。我们发现EHD1-4直接与Ankyrin结合，首次提供了这些分子在原代心肌细胞中表达和定位的信息，并证明EHD1-4与ankyrin-B在心肌细胞核周区域共表达。值得注意的是，在缺乏ankyrin-B的动物模型中，多种EHD蛋白的表达增加，并且EHD3缺陷的心肌细胞显示出ankyrin-B的异常定位和Na/Ca交换器表达和功能的选择性丧失。最后，我们报道了心肌梗死后EHD表达的显著调节，提示这些蛋白可能在调节正常和疾病心脏的膜兴奋性方面发挥关键作用。结论：我们的发现识别和表征了一类新的心脏运输蛋白，定义了第一组与基于锚蛋白的靶向网络相关的蛋白质，并确定了潜在的新靶点来调节疾病中的膜兴奋性。值得注意的是，这些数据提供了EHD蛋白和人类疾病模型之间的第一个联系。(中国保监会决议2010；107：84-95。)
Rationale: Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health and disease are maintained by a complex ensemble of intracellular targeting, scaffolding, recycling, and degradation pathways. Surprisingly, despite decades of research linking dysfunction in membrane protein trafficking with human cardiovascular disease, essentially nothing is known regarding the molecular identity or function of these intracellular targeting pathways in excitable cardiomyocytes.Objective: We sought to discover novel pathways for membrane protein targeting in primary cardiomyocytes.Methods and Results: We report the initial characterization of a large family of membrane trafficking proteins in human heart. We used a tissue-wide screen for novel ankyrin-associated trafficking proteins and identified 4 members of a unique Eps15 homology (EH) domain-containing protein family (EHD1, EHD2, EHD3, EHD4) that serve critical roles in endosome-based membrane protein targeting in other cell types. We show that EHD1-4 directly associate with ankyrin, provide the first information on the expression and localization of these molecules in primary cardiomyocytes, and demonstrate that EHD1-4 are coexpressed with ankyrin-B in the myocyte perinuclear region. Notably, the expression of multiple EHD proteins is increased in animal models lacking ankyrin-B, and EHD3-deficient cardiomyocytes display aberrant ankyrin-B localization and selective loss of Na/Ca exchanger expression and function. Finally, we report significant modulation of EHD expression following myocardial infarction, suggesting that these proteins may play a key role in regulating membrane excitability in normal and diseased heart.Conclusions: Our findings identify and characterize a new class of cardiac trafficking proteins, define the first group of proteins associated with the ankyrin-based targeting network, and identify potential new targets to modulate membrane excitability in disease. Notably, these data provide the first link between EHD proteins and a human disease model. (Circ Res. 2010; 107: 84-95.)