STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function.
STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function.
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DOI：
10.1186/2044-5040-1-16
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发表时间：
2011-04-04
期刊：
影响因子：
4.9
通讯作者：
Bultynck G
中科院分区：
文献类型：
--
作者：
Kiviluoto S;Decuypere JP;De Smedt H;Missiaen L;Parys JB;Bultynck G
基质相互作用分子（Stromal interaction molecules，STIM）是一种内质网Ca ~（2+）传感器，在非兴奋细胞中控制钙库操纵的Ca ~（2+）内流（store-operated Ca ~（2+）entry，SOCE）和Ca ~（2+）释放激活的Ca ~（2+）通道（Ca ~（2+）-release activated Ca ~（2+）channel，CRAC）。STIM蛋白靶向质膜中的Orai 1 -3四聚体Ca 2+渗透通道。结构-功能分析揭示了STIM激活奥赖的分子决定因素和关键步骤。最近，发现STIM 1在骨骼肌中以高水平表达，控制肌肉功能和特性。除了奥赖通道之外，新的STIM靶点正在出现。在这里，我们将重点关注STIM 1在骨骼肌结构，发育和功能中的作用。支撑肌肉生理学的分子机制指向STIM 1控制的SOCE驱动Ca 2 +/钙调神经磷酸酶/活化T细胞核因子（NFAT）依赖性形态发生重塑程序并支持足够的肌浆网（SR）Ca 2+储存填充的重要作用。同样在我们的手中，STIM 1在C2 C12细胞体外肌生成的初始阶段瞬时上调。这些细胞中STIM 1的分子靶标可能涉及奥赖通道和典型瞬时受体电位（TRPC）通道TRPC 1和TRPC 3。骨骼肌中SOCE激活的快速动力学似乎取决于三联体连接的形成，有利于STIM 1-蛋白复合物与质膜Ca 2+内流通道的预定位和/或预形成。此外，Orai 1介导的Ca 2+内流似乎是必不可少的控制静息Ca 2+浓度和适当的SR Ca 2+填充。因此，通过STIM 1依赖性激活来自T-小管系统的SOCE的Ca 2+内流可以在肌肉刺激期间回收细胞外Ca 2+损失，从而维持SR Ca 2+储存和肌肉功能的适当填充。重要的是，营养不良病理学的小鼠模型，如杜氏肌营养不良，指向通过Orai 1和/或TRPC通道的增强的Ca 2+内流，导致Ca 2+依赖性细胞凋亡和肌肉变性。此外，人类肌病与功能障碍性SOCE相关。携带功能丧失Orai 1突变的免疫缺陷患者发生肌病，而患有杜氏肌营养不良症的患者显示其Ca 2+处理蛋白（包括STIM蛋白）的改变。在任何情况下，负责人类骨骼肌中的SOCE和肌营养不良症患者的失调SOCE的分子决定因素需要进一步检查。
Stromal interaction molecules (STIM) were identified as the endoplasmic-reticulum (ER) Ca2+ sensor controlling store-operated Ca2+ entry (SOCE) and Ca2+-release-activated Ca2+ (CRAC) channels in non-excitable cells. STIM proteins target Orai1-3, tetrameric Ca2+-permeable channels in the plasma membrane. Structure-function analysis revealed the molecular determinants and the key steps in the activation process of Orai by STIM. Recently, STIM1 was found to be expressed at high levels in skeletal muscle controlling muscle function and properties. Novel STIM targets besides Orai channels are emerging. Here, we will focus on the role of STIM1 in skeletal-muscle structure, development and function. The molecular mechanism underpinning skeletal-muscle physiology points toward an essential role for STIM1-controlled SOCE to drive Ca2+/calcineurin/nuclear factor of activated T cells (NFAT)-dependent morphogenetic remodeling programs and to support adequate sarcoplasmic-reticulum (SR) Ca2+-store filling. Also in our hands, STIM1 is transiently up-regulated during the initial phase of in vitro myogenesis of C2C12 cells. The molecular targets of STIM1 in these cells likely involve Orai channels and canonical transient receptor potential (TRPC) channels TRPC1 and TRPC3. The fast kinetics of SOCE activation in skeletal muscle seem to depend on the triad-junction formation, favoring a pre-localization and/or pre-formation of STIM1-protein complexes with the plasma-membrane Ca2+-influx channels. Moreover, Orai1-mediated Ca2+ influx seems to be essential for controlling the resting Ca2+ concentration and for proper SR Ca2+ filling. Hence, Ca2+ influx through STIM1-dependent activation of SOCE from the T-tubule system may recycle extracellular Ca2+ losses during muscle stimulation, thereby maintaining proper filling of the SR Ca2+ stores and muscle function. Importantly, mouse models for dystrophic pathologies, like Duchenne muscular dystrophy, point towards an enhanced Ca2+ influx through Orai1 and/or TRPC channels, leading to Ca2+-dependent apoptosis and muscle degeneration. In addition, human myopathies have been associated with dysfunctional SOCE. Immunodeficient patients harboring loss-of-function Orai1 mutations develop myopathies, while patients suffering from Duchenne muscular dystrophy display alterations in their Ca2+-handling proteins, including STIM proteins. In any case, the molecular determinants responsible for SOCE in human skeletal muscle and for dysregulated SOCE in patients of muscular dystrophy require further examination.
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影响因子：
64.5
作者：
Feng M;Grice DM;Faddy HM;Nguyen N;Leitch S;Wang Y;Muend S;Kenny PA;Sukumar S;Roberts-Thomson SJ;Monteith GR;Rao R
通讯作者：
Rao R
影响因子：
8.7
作者：
通讯作者：
--
影响因子：
4.8
作者：
Darbellay, Basile;Arnaudeau, Serge;Bernheim, Laurent
通讯作者：
Bernheim, Laurent
影响因子：
4
作者：
Cárdenas, C;Liberona, JL;Jaimovich, E
通讯作者：
Jaimovich, E
DOI：
10.1073/pnas.0608358103
发表时间：
2006-11-07
影响因子：
11.1
作者：
Baba, Yoshihiro;Hayashit, Kenji;Kurosaki, Tomohiro
通讯作者：
Kurosaki, Tomohiro