Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes.
Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes.
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DOI：
10.2741/e344
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发表时间：
2011-06-01
期刊：
影响因子：
--
通讯作者：
Lin CI
中科院分区：
文献类型：
--
作者：
Chan FC;Cheng CP;Wu KH;Chen YC;Hsu CH;Gustafson-Wagner EA;Lin JL;Wang Q;Lin JJ;Lin CI
小鼠Xin-alpha（mXin-alpha）编码一种定位于闰盘（ICD）的含有Xin重复序列的肌动蛋白结合蛋白。mXin-alpha消融逐渐导致ICD结构破坏、心脏肥大和心肌病伴成年期传导缺陷。这种传导缺陷可能是由于ICD结构缺陷和/或细胞电生理特性变化。在这里，我们发现，尽管正常的ICD结构，幼年mXina-null心肌细胞（来自3~4周龄小鼠）表现出瞬态外向K+电流（ITO）的显着减少，类似于成年突变细胞。幼年而非成年突变心肌细胞的延迟整流钾电流也有显着减少。相反，突变的成年心室肌细胞的内向整流钾电流（IK 1）的超极化显着减少。这些共同解释了在幼年mXin-alpha-null细胞中观察到的动作电位时程（APD）的延长和早期后去极化的易发性。有趣的是，幼年mXin-alpha-null心肌细胞的细胞内Ca 2+瞬变幅度显著降低，而L型Ca 2+电流无变化，表明APD延长并没有促进心肌肥大的细胞内Ca 2+增加。幼年mXin-alpha-null心室的膜相关Kv通道相互作用蛋白2（ITO的辅助亚基）和细丝蛋白（肌动蛋白交联蛋白）水平降低。我们进一步表明，mXin-alpha与两种蛋白质相互作用，为ITO表面表达提供了一种新的机制
Mouse Xin-alpha (mXin-alpha) encodes a Xin repeat-containing, actin-binding protein localized to the intercalated disc (ICD). Ablation of mXin-alpha progressively leads to disrupted ICD structure, cardiac hypertrophy and cardiomyopathy with conduction defects during adulthood. Such conduction defects could be due to ICD structural defects and/or cell electrophysiological property changes. Here, we showed that despite the normal ICD structure, juvenile mXina-null cardiomyocytes (from 3~4-week-old mice) exhibited a significant reduction in the transient outward K+ current (ITO), similar to adult mutant cells. Juvenile but not adult mutant cardiomyocytes also had a significant reduction in the delayed rectifier K+ current. In contrast, the mutant adult ventricular myocytes had a significant reduction in the inward rectifier K+ current (IK1) on hyperpolarization. These together could account for the prolongation of action potential duration (APD) and the ease of developing early afterdepolarization observed in juvenile mXin-alpha-null cells. Interestingly, juvenile mXin-alpha-null cardiomyocytes had a notable decrease in the amplitude of intracellular Ca2+ transient and no change in the L-type Ca2+ current, suggesting that the prolonged APD did not promote an increase in intracellular Ca2+ for cardiac hypertrophy. Juvenile mXin-alpha-null ventricles had reduced levels of membrane-associated Kv channel interacting protein 2, an auxiliary subunit of ITO, and filamin, an actin cross-linking protein. We further showed that mXin-alpha interacted with both proteins, providing a novel mechanism for ITO surface expression