STIM1-and Orai1-dependent Store-operated Calcium Entry Regulates Human Myoblast Differentiation
STIM1-and Orai1-dependent Store-operated Calcium Entry Regulates Human Myoblast Differentiation
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DOI：
10.1074/jbc.m806726200
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发表时间：
2009-02-20
影响因子：
4.8
通讯作者：
Bernheim, Laurent
中科院分区：
文献类型：
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作者：
Darbellay, Basile;Arnaudeau, Serge;Bernheim, Laurent
我们以前对人成肌细胞的研究表明，超极化后[Ca2 +]（in）的升高涉及钙库操纵的Ca2+进入（SOCE）通道诱导成肌细胞分化。对SOCE通路理解的进展使我们更精确地研究其在出生后人类成肌细胞分化中的作用。我们发现，由STIM 1（激活奥赖Ca 2+通道的内质网Ca 2+传感器）协调的SOCE至关重要。沉默STIM1、Orai1或Orai3可降低SOCE振幅和成肌细胞分化，而Orai2敲低则无影响。相反，STIM 1与Orai 1的过表达增加了SOCE并加速了成肌细胞分化。STIM1或Orai1沉默降低静息[Ca2+]（in）和细胞内Ca2+库含量，但这些参数的校正并不能挽救成肌细胞分化。值得注意的是，SOCE幅度与成肌细胞分化的两个早期标志物MEF 2和肌细胞生成素的表达呈线性相关，而不管STIM 1或奥赖亚型被沉默。出乎意料的是，我们发现超极化也依赖于SOCE，将SOCE置于控制成肌细胞分化的信号级联中K+通道激活的上游。这些发现表明，STIM1和Orai1是诱导人成肌细胞分化的关键分子。
Our previous work on human myoblasts suggested that a hyperpolarization followed by a rise in [Ca2(+)](in) involving store-operated Ca2+ entry (SOCE) channels induced myoblast differentiation. Advances in the understanding of the SOCE pathway led us to examine more precisely its role in post-natal human myoblast differentiation. We found that SOCE orchestrated by STIM1, the endoplasmic reticulum Ca2+ sensor activating Orai Ca2+ channels, is crucial. Silencing STIM1, Orai1, or Orai3 reduced SOCE amplitude and myoblast differentiation, whereas Orai2 knockdown had no effect. Conversely, overexpression of STIM1 with Orai1 increased SOCE and accelerated myoblast differentiation. STIM1 or Orai1 silencing decreased resting [Ca2+](in) and intracellular Ca2+ store content, but correction of these parameters did not rescue myoblast differentiation. Remarkably, SOCE amplitude correlated linearly with the expression of two early markers of myoblast differentiation, MEF2 and myogenin, regardless of the STIM1 or Orai isoform that was silenced. Unexpectedly, we found that the hyperpolarization also depends on SOCE, placing SOCE upstream of K+ channel activation in the signaling cascade that controls myoblast differentiation. These findings indicate that STIM1 and Orai1 are key molecules for the induction of human myoblast differentiation.