ATP and noradrenaline activate CREB in astrocytes via noncanonical Ca2+ and cyclic AMP independent pathways
ATP and noradrenaline activate CREB in astrocytes via noncanonical Ca2+ and cyclic AMP independent pathways
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DOI：
10.1002/glia.22352
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发表时间：
2012-09-01
期刊：
影响因子：
6.2
通讯作者：
Galea, Elena
中科院分区：
文献类型：
--
作者：
Carriba, Paulina;Pardo, Luis;Galea, Elena
在神经元中，CREB通过协调将经验转化为活动依赖（即由神经递质驱动）的可塑性相关基因转录，从而有助于学习和记忆。活性依赖性creb触发的转录需要环AMP/蛋白激酶A和Ca2+/钙调磷酸酶通过creb调节的转录共激活因子（CRTC）协同作用。然而，目前尚不清楚星形胶质细胞中是否存在类似的分子序列，尽管这些细胞对大脑可塑性的贡献是毋庸置疑的。在这里，我们试图确定ATP和去甲肾上腺素是否以及如何在大鼠皮质星形胶质细胞培养中引起creb依赖性转录。这两种递质均诱导CREB磷酸化（Western Blots）、CREB依赖性转录（CREB荧光素酶报告基因检测）和Bdnf的转录，Bdnf是突触可塑性的典型调节因子（定量RT-PCR）。我们在级联的最上层发现了Ca2+和二酰基甘油不依赖的蛋白激酶C，导致creb依赖性转录。值得注意的是，creb依赖性转录部分依赖于ERK1/2和CRTC，但不依赖于环AMP/蛋白激酶A或Ca2+/钙调磷酸酶。我们得出结论，ATP和去甲肾上腺素通过非典型蛋白激酶c激活皮质星形胶质细胞中creb依赖的转录。相关的是，所涉及的信号与神经元中描述的信号截然不同，因为Ca2+和循环amp依赖通路在CRTC上没有收敛，而且，CRTC发挥调节作用而不是中心作用。因此，我们的数据表明，CREB在可塑性中存在一种替代的、非神经元的、基于胶质的作用。(c) 2012 Wiley期刊有限公司
In neurons, it is well established that CREB contributes to learning and memory by orchestrating the translation of experience into the activity-dependent (i.e., driven by neurotransmitters) transcription of plasticity-related genes. The activity-dependent CREB-triggered transcription requires the concerted action of cyclic AMP/protein kinase A and Ca2+/calcineurin via the CREB-regulated transcription co-activator (CRTC). It is not known, however, whether a comparable molecular sequence occurs in astrocytes, despite the unquestionable contribution of these cells to brain plasticity. Here we sought to determine whether and how ATP and noradrenaline cause CREB-dependent transcription in rat cortical astrocyte cultures. Both transmitters induced CREB phosphorylation (Western Blots), CREB-dependent transcription (CRE-luciferase reporter assays), and the transcription of Bdnf, a canonical regulator of synaptic plasticity (quantitative RT-PCR). We indentified a Ca2+ and diacylglycerol-independent protein kinase C at the uppermost position of the cascade leading to CREB-dependent transcription. Notably, CREB-dependent transcription was partially dependent on ERK1/2 and CRTC, but independent of cyclic AMP/protein kinase A or Ca2+/calcineurin. We conclude that ATP and noradrenaline activate CREB-dependent transcription in cortical astrocytes via an atypical protein kinase C. It is of relevance that the signaling involved be starkly different to the one described in neurons since there is no convergence of Ca2+ and cyclic AMP-dependent pathways on CRTC, which, moreover, exerts a modulatory rather than a central role. Our data thus point to the existence of an alternative, non-neuronal, glia-based role of CREB in plasticity. (c) 2012 Wiley Periodicals, Inc.