Mitochondrial calcium signaling mediates rhythmic extracellular ATP accumulation in suprachiasmatic nucleus astrocytes.
Mitochondrial calcium signaling mediates rhythmic extracellular ATP accumulation in suprachiasmatic nucleus astrocytes.
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DOI：
10.1523/jneurosci.6576-10.2011
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发表时间：
2011-06-08
期刊：
影响因子：
--
通讯作者：
Zoran MJ
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文献类型：
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作者：
Burkeen JF;Womac AD;Earnest DJ;Zoran MJ
位于视交叉上核（SCN）内的主昼夜节律起搏器控制哺乳动物大脑中的神经和神经内分泌节律。星形胶质细胞在SCN中是丰富的，并且这种细胞类型在时钟基因表达和三磷酸腺苷（ATP）的细胞外积累中显示昼夜节律。尽管如此，细胞内的信号通路，连接SCN时钟的昼夜节律在细胞外ATP积累仍然不清楚。由于ATP从星形胶质细胞的释放是一个钙依赖性的过程，我们研究了细胞内Ca2+和ATP积累之间的关系，并已证明，在大鼠SCN 2.2细胞培养物中，细胞内Ca2+水平波动与ATP的节律性积累的反相关系。此外，线粒体Ca2+水平的节奏和最大的精确反相峰在胞浆Ca2+。相反，我们的发现，峰值线粒体Ca2+发生在最大的细胞外ATP积累表明这些细胞节律之间的联系。线粒体Ca 2+单向转运体的抑制破坏了ATP的节律性产生和细胞外积累。ATP、钙和生物钟影响细胞分裂，并与细胞死亡过程有关。尽管如此，细胞周期阻滞并没有破坏细胞外ATP的有节奏的积累，并且与SCN 2.2细胞培养物中的半胱天冬酶活性无关。总之，这些结果表明，线粒体Ca2+介导SCN 2.2的细胞外ATP积累的节奏，并建议在SCN时钟功能的昼夜节律gliotransmission的作用。
The master circadian pacemaker located within the suprachiasmatic nuclei (SCN) controls neural and neuroendocrine rhythms in the mammalian brain. Astrocytes are abundant in the SCN and this cell type displays circadian rhythms in clock gene expression and extracellular accumulation of adenosine triphosphate (ATP). Still, the intracellular signaling pathways that link the SCN clockworks to circadian rhythms in extracellular ATP accumulation remain unclear. Since ATP release from astrocytes is a calcium-dependent process, we investigated the relationship between intracellular Ca2+ and ATP accumulation and have demonstrated that intracellular Ca2+ levels fluctuate in an antiphase relationship with rhythmic ATP accumulation in rat SCN2.2 cell cultures. Furthermore, mitochondrial Ca2+ levels were rhythmic and maximal in precise antiphase with the peak in cytosolic Ca2+. In contrast, our finding that peak mitochondrial Ca2+ occurred during maximal extracellular ATP accumulation suggests a link between these cellular rhythms. Inhibition of the mitochondrial Ca2+uniporter disrupted the rhythmic production and extracellular accumulation of ATP. ATP, calcium and the biological clock affect cell division and have been implicated in cell death processes. Nonetheless, rhythmic extracellular ATP accumulation was not disrupted by cell cycle arrest and was not correlated with caspase activity in SCN2.2 cell cultures. Taken together, these results demonstrate that mitochondrial Ca2+mediates SCN2.2 rhythms in extracellular ATP accumulation and suggest a role for circadian gliotransmission in SCN clock function.