CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor
CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor
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DOI：
10.1007/s00018-016-2397-5
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发表时间：
2017-03-01
影响因子：
8
通讯作者：
Masgrau, R.
中科院分区：
文献类型：
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作者：
Eraso-Pichot, A.;Larramona-Arcas, R.;Masgrau, R.
星形胶质细胞的兴奋性依赖于胞质钙的增加作为关键机制，星形胶质细胞有助于突触传递，从而促进学习和记忆。虽然记忆经验是神经科学的基石，但由于递质激活神经元中的基因表达，星形胶质细胞的长期适应性可塑性尚未被描述。在这里，我们研究了转录因子 CREB 是否介导星形胶质细胞中的适应性可塑性现象。我们发现 CREB 依赖性转录的激活降低了 ATP、去甲肾上腺素或内皮素-1 诱导的钙反应。至于机制，VP16-CREB（一种组成型活性 CREB 突变体）的表达对基础细胞质钙水平、细胞外钙进入或溶酶体相关酸性储存的钙动员没有影响。相反，VP16-CREB上调了sigma-1受体表达，从而增加了内质网钙的释放和线粒体对钙的吸收。星形胶质细胞中 VP16-CREB 表达后，体内 Sigma-1 受体也上调。我们得出的结论是，CREB 通过增加内质网-线粒体界面的钙信号传导来降低星形胶质细胞的反应性，这可能是一种基于星形胶质细胞的长期抑郁形式。
Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression.