On the role of junctin in cardiac Ca2+ handling, contractility, and heart failure
On the role of junctin in cardiac Ca2+ handling, contractility, and heart failure
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DOI：
10.1152/ajpheart.01187.2006
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发表时间：
2007-07-01
影响因子：
4.8
通讯作者：
Neumann, Joachim
中科院分区：
文献类型：
--
作者：
Gergs, Ulrich;Berndt, Tobias;Neumann, Joachim
Junctin是一种跨膜蛋白，位于心脏连接肌浆网（SR），与钙释放通道、三聚体蛋白和钙螯合蛋白形成四元复合物。该复合物内受损的蛋白质相互作用可能改变Ca2+释放通道的Ca2+敏感性，并可能导致心脏功能障碍，包括肥大、收缩性降低和异常Ca2+瞬变。为了研究心力衰竭中连接蛋白的表达，并与三聚蛋白进行比较，我们测量了正常和衰竭人类心脏SR中这些蛋白质的水平。连接蛋白低于我们在来自衰竭人类心脏的SR膜中的检测水平，而三聚体蛋白下调了22%。为了更好地了解连接蛋白在调节Ca2+稳态和心肌细胞收缩中的作用，我们使用腺病毒方法在分离的大鼠心肌细胞中过表达连接蛋白。编码绿色荧光蛋白的重组腺病毒作为对照。用表达连接蛋白的病毒感染心肌细胞导致连接蛋白的RNA和蛋白表达增加。Ca2+瞬变显示最大Ca2+幅度降低，心肌细胞的收缩力受到抑制。我们的研究结果表明，连接蛋白的表达增加与受损的Ca2+稳态。因此，人类心力衰竭中连接蛋白的下调可能是一种代偿机制。
Junctin is a transmembrane protein located at the cardiac junctional sarcoplasmic reticulum (SR) and forms a quaternary complex with the Ca2+ release channel, triadin and calsequestrin. Impaired protein interactions within this complex may alter the Ca2+ sensitivity of the Ca2+ release channel and may lead to cardiac dysfunction, including hypertrophy, depressed contractility, and abnormal Ca2+ transients. To study the expression of junctin and, for comparison, triadin, in heart failure, we measured the levels of these proteins in SR from normal and failing human hearts. Junctin was below our level of detection in SR membranes from failing human hearts, and triadin was downregulated by 22%. To better understand the role of junctin in the regulation of Ca2+ homeostasis and contraction of cardiac myocytes, we used an adenoviral approach to overexpress junctin in isolated rat cardiac myocytes. A recombinant adenovirus encoding the green fluorescent protein served as a control. Infection of myocytes with the junctin-expressing virus resulted in an increased RNA and protein expression of junctin. Ca2+ transients showed a decreased maximum Ca2+ amplitude, and contractility of myocytes was depressed. Our results demonstrate that an increased expression of junctin is associated with an impaired Ca2+ homeostasis. Downregulation of junctin in human heart failure may thus be a compensatory mechanism.