Extracellular adenosine 5'-triphosphate elicits the expression of brain-derived neurotrophic factor exon IV mRNA in rat astrocytes
Extracellular adenosine 5'-triphosphate elicits the expression of brain-derived neurotrophic factor exon IV mRNA in rat astrocytes
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DOI：
10.1002/glia.20704
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发表时间：
2008-10-01
期刊：
影响因子：
6.2
通讯作者：
Tsuda, Masaaki
中科院分区：
文献类型：
--
作者：
Takasaki, Ichiro;Takarada, Satoko;Tsuda, Masaaki
最近越来越多的证据表明，ATP在神经元与神经胶质的通讯中起着重要作用。在这项研究中，作者证明了细胞外ATP在原代培养的大鼠皮层星形胶质细胞中诱导脑源性神经营养因子（BDNF）的基因表达，特别是BDNF外显子IV mRNA，但在神经元中没有。为了研究ATP诱导BDNF外显子IV mRNA表达的机制，作者使用永生化星形胶质细胞系rgc -12。ATP剂量依赖性地增加BDNF外显子IV mRNA的表达并激活BDNF启动子IV。P2Y受体激动剂（ADP和2MeS-ADP）诱导BDNF外显子IV mRNA的表达，而P2X受体激动剂（α - β - MeATP）不诱导BDNF外显子IV mRNA的表达。此外，atp诱导的BDNF外显子IV mRNA上调被P2Y拮抗剂（MRS2179）抑制，而不被P2X拮抗剂（TNP-ATP和PPADS）抑制。这些发现表明P2Y受体参与了atp诱导的BDNF基因转录。在本研究中检测的信号转导抑制剂中，细胞内Ca2+螯合剂（BAPTA-AM）和Ca2+/钙调素依赖性激酶（CaM激酶）抑制剂（KN-93和W-7）减弱了atp诱导的BDNF外显子IV mRNA上调。ATP瞬间诱导camp响应元件结合蛋白（CREB）的磷酸化。atp诱导的CREB磷酸化被P2Y拮抗剂、BAPTA-AM和CaM激酶抑制剂抑制。显性CREB阴性突变体的过表达降低了BDNF启动子IV的激活，减弱了BDNF外显子IV mRNA表达的上调。这些结果表明，ATP通过P2Y受体诱导BDNF表达，随后激活CaM激酶和CREB。这些机制可能有助于神经元-神经胶质网络的增强。(c) 2008 Wiley-Liss, Tric。
A growing body of recent evidence indicates that ATP plays an important role in neuronal-glial communications. In this study, the authors demonstrated that extracellular ATP elicits the gene expression of brain-derived neurotrophic factor (BDNF), especially BDNF exon IV mRNA, in primary cultured rat cortical astrocytes but not in neurons. To investigate the mechanism by which ATP induces BDNF exon IV mRNA expression, the authors used immortalized astrocyte cell line RCG-12. ATP dose-dependently increased the expression of BDNF exon IV mRNA and activated BDNF promoter IV. P2Y receptor agonists (ADP and 2MeS-ADP) but not a P2X receptor agonist (alpha beta MeATP) induced the expression of BDNF exon IV mRNA. Moreover, ATP-induced BDNF exon IV mRNA upregulation was inhibited by a P2Y antagonist (MRS2179) but not by P2X antagonists (TNP-ATP and PPADS). These findings suggest the involvement of P2Y receptors in the ATP-induced transcription of the BDNF gene. Among the signal transduction inhibiters examined in this study, intracellular Ca2+ chelator (BAPTA-AM) and Ca2+/calmodulin-dependent kinase (CaM kinase) inhibitors (KN-93 and W-7) attenuated ATP-induced BDNF exon IV mRNA upregulation. ATP transiently induced the phosphorylation of cAMP-responsive element-binding protein (CREB). ATP-induced CREB phosphorylation was repressed by P2Y antagonists, BAPTA-AM, and CaM kinase inhibitors. Overexpression of dominant negative CREB mutants reduced the activation of BDNF promoter IV and attenuated the upregulation of BDNF exon IV mRNA expression. These results suggest that ATP induces BDNF expression through P2Y receptor followed by the activation of CaM kinase and CREB in astrocytes. These mechanisms are likely to contribute to the enhancement of neuronal-glial networks. (c) 2008 Wiley-Liss, Tric.