Xin Scaffolding Proteins and Arrhythmias.
Xin Scaffolding Proteins and Arrhythmias.
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发表时间：
2013-10
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通讯作者：
Qinchuan Wang;J. J. Lin-J.
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作者：
Qinchuan Wang;J. J. Lin-J.
间盘(Intercalated Disk，ICD)是心肌中一种独特的特殊结构，在心肌细胞间传递机械力和电脉冲。最近的研究还表明，ICD通过支架/锚定蛋白，可以在空间上组织和维持控制心脏动作电位所需的关键离子通道组装。这些过程中的缺陷可能导致心律失常和心源性猝死。例如，人类NaV1.5 E1053K错义突变破坏了其与ankyrin G的结合，ankyrin G是将NaV1.5靶向ICD和心肌细胞横管/侧膜所需的支架蛋白。因此，这种突变会导致Brugada综合征[1]。相反，肌动蛋白G缺乏的心肌细胞表现出NAV1.5表面表达和定位减少以及INA电流密度降低[2]。这些发现清楚地证明了骨架蛋白G(一种支架蛋白)功能障碍与人类心律失常之间的联系。另一种支架蛋白突触相关蛋白97(SAP97)是膜相关鸟氨酸蛋白(MAGUK)家族的成员，它优先定位于ICD，并通过其PDZ结构域与NaV1.5的最后3个残基(Ser-IleVal)相互作用，负责将NaV1.5池锚定到ICD上。因此，有待解决的问题是，这些支架蛋白在靶向和维持ICD膜上的NaV1.5方面的作用是互补的、合作的、竞争的还是多余的。
Intercalated disc (ICD), a unique specialized structure in cardiac muscle, transmits mechanical force and electrical impulses among cardiomyocytes. Recent studies also suggest that ICD, via scaffolding/anchoring proteins, can spatially organize and maintain key ion channel assemblies required for controlling the cardiac action potential. Defects in these processes can lead to arrhythmias and cardiac sudden death. For example, human Nav1.5 E1053K missense mutation disrupts its binding to ankyrin G, a scaffolding protein required for targeting Nav1.5 to ICD and transverse (T) tubule/lateral membranes of cardiomyocytes. As a consequence, this mutation causes Brugada syndrome [1]. Conversely, ankyrin G-deficient cardiomyocytes show reduced Nav1.5 surface expression and localization as well as reduced INa current density [2]. These findings clearly demonstrate a link between ankyrin G (a scaffolding protein) dysfunction and human arrhythmias. Another scaffolding protein, synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase (MAGUK) family, is preferentially localized to the ICDs and responsible for anchoring the pool of Nav1.5 to the ICDs through its PDZ domain interacting with the 3 last residues (Ser-IleVal) of Nav1.5 [3]. Thus, the question remaining to be addressed is whether the roles of these scaffolding proteins in targeting and maintaining Nav1.5 to the ICD membrane are complementary, cooperative, competitive or redundant.