New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD
New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD
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DOI：
10.1007/s10974-006-9085-2
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发表时间：
2006-05-01
影响因子：
2.7
通讯作者：
Cognard, Christian
中科院分区：
文献类型：
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作者：
Constantin, Bruno;Sebille, Stephane;Cognard, Christian
Duchenne型肌营养不良症（DMD）的钙处理不当表明，肌营养不良蛋白，一种膜相关的细胞骨架蛋白，可以调节钙信号级联反应，如钙进入。人DMD肌管中的钙超载依赖于它们的收缩活性，这表明在收缩和/或钙释放期间通道被激活。在肌营养不良蛋白缺陷的肌管中，微小肌营养不良蛋白的强制表达，重新激活肌营养不良蛋白相关蛋白的适当肌膜表达，并恢复胞质溶胶中的正常钙处理。此外，重组迷你肌营养不良蛋白减少了跨肌膜的钙库操作的钙内流，并在此内流过程中的线粒体钙摄取。依赖于IP 3R的钙释放的缓慢组分以及IP 3的产生也通过微小肌营养不良蛋白的表达降低至正常水平。我们的研究提供了一个新的模型，跨膜钙内流和IP 3依赖的钙释放的肌营养不良蛋白为基础的细胞骨架（DBC）的会聚调节。我们还建议这样的通道与DBC的分子关联，这可能为组装调节通道活性的多蛋白信号复合物提供支架。这表明这种分子关联的丧失可能参与DMD肌细胞中观察到的钙稳态的改变。
Calcium mishandling in Duchenne muscular dystrophy (DMD) suggested that dystrophin, a membrane-associated cytoskeleton protein, may regulate calcium-signalling cascades such as calcium entries. Calcium overload in human DMD myotubes is dependent on their contractile activity suggesting the involvement of channels being activated during contraction and/or calcium release. Forced expression of mini-dystrophin in dystrophin-deficient myotubes, reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and restores normal calcium handling in the cytosol. Furthermore, the recombinant mini-dystrophin reduced the store-operated calcium influx across the sarcolemma, and the mitochondrial calcium uptake during this influx. A slow component of calcium release dependent on IP3R, as well as the production of IP3, were also reduced to normal levels by expression of mini-dystrophin. Our studies provide a new model for the convergent regulation of transmembrane calcium influx and IP3-dependent calcium release by the dystrophin-based cytoskeleton (DBC). We also suggest molecular association of such channels with DBC which may provide the scaffold for assembling a multiprotein-signalling complex that modulates the channel activity. This suggests that the loss of this molecular association could participate in the alteration of calcium homeostasis observed in DMD muscle cells.