Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis
Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis
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DOI：
10.1038/sj.bjp.0701294
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发表时间：
1997-08-01
影响因子：
7.3
通讯作者：
Abbracchio, MP
中科院分区：
文献类型：
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作者：
Bolego, C;Ceruti, S;Abbracchio, MP
1用α，β-亚甲基ATP（α，β-meATP）或碱性成纤维细胞生长因子（bFGF）短暂刺激大鼠星形胶质细胞，三天后，细胞形态发生分化，星形胶质细胞突起明显延长。P2受体拮抗剂苏拉明阻止α，β-meATP诱导的星形胶质细胞延长，但不能阻止bFGF诱导的星形胶质细胞延长。在ATP和其他P2受体激动剂（β、γ meATP、ADP β S、2 meSATP和UTP，在较小程度上）中也观察到对星形胶质细胞延长的类似作用。2百日咳毒素完全消除了α、β meATP诱导的作用，但没有bFGF诱导的作用。α，β-meATP对环AMP产生没有作用：类似地，新霉素对嘌呤类似物诱导的过程的延长没有作用，表明腺苷酸环化酶和磷脂酶C可能不参与α，β-meATP诱导的作用（还参见Centemeri等人的随附论文，1997年）。酪氨酸激酶抑制剂染料木黄酮大大降低了bFGF诱导的星形胶质细胞延长，但对α，β-meATP诱导的星形胶质细胞延长没有影响。3用α，β-meATP刺激培养物可快速且浓度依赖性地增加细胞释放的[H-3]-花生四烯酸（AA），表明磷脂酶A（2）（PLA（2））的激活可能与嘌呤类似物引起的长期功能效应有关。连续外源性添加AA显著延长星形胶质细胞突起。此外，各种PLA（2）抑制剂（如米帕林和地塞米松）阻止了早期α，β-meATP诱导的[H-3]-AA释放和/或相关的长期形态学变化，而不影响bFGF诱导的星形胶质细胞伸长。最后，蛋白激酶C（PKC）抑制剂H7完全消除了α，β-meATP-但不是bFGF-诱导的效应。4 α，β-meATP和bFGF都能快速和短暂地诱导Fos和Jun. c-fos和c-jun的核积累嘌呤类似物诱导可以完全阻止苏拉明预处理。相反，bFGF的作用不受这种P2受体拮抗剂的影响。5得出结论，星形胶质细胞的α，β-meATP和bFGF形态分化通过独立的转导途径发生。对于嘌呤类似物，信号传导涉及G（i）/G（o）蛋白偶联的P2 Y受体，其可能与PLA（2）的活化有关（推测涉及花生四烯酸敏感的PKC）;对于bFGF，涉及酪氨酸激酶受体。这两种途径在一些共同的细胞内靶点上合并，如诱导初级反应基因所示，这反过来可能调节晚期反应基因，介导星形胶质细胞的长期表型变化。6这些发现表明P2受体是反应性星形胶质细胞增生药理学调节的新靶点，这在以退行性事件为特征的神经系统疾病中具有有趣的意义。
1 A brief challenge of rat astrocytes with either alpha,beta-methyleneATP (alpha,beta-meATP) or basic fibroblast growth factor (bFGF) resulted, three days later, in morphological differentiation of cells, as shown by marked elongation of astrocytic processes, The P2 receptor antagonist suramin prevented alpha,beta-meATP- but not bFGF-induced astrocytic elongation. Similar effects on astrocytic elongation were also observed with ATP and other P2 receptor agonists (beta,gamma meATP, ADP beta S, 2meSATP and, to a lesser extent, UTP).2 Pertussis toxin completely abolished alpha,beta meATP- but not bFGF-induced effects. No effects were exerted by cr,beta-meATP on cyclic AMP production: similarly, neomycin had no effects on elongation of processes induced by the purine analogue, suggesting that adenylyl cyclase and phospholipase C are probably not involved in alpha,beta-meATP-induced effects (see also the accompanying paper by Centemeri et ai., 1997). The tyrosine-kinase inhibitor genistein greatly reduced bFGF-but not alpha,beta-meATP-induced astrocytic elongation.3 Challenge of cultures with alpha,beta-meATP rapidly and concentration-dependently increased [H-3]-arachidonic acid (AA) release from cells, suggesting that activation of phospholipase A(2) (PLA(2)) may be involved in the long-term functional effects evokeded by purine analogues. Consistently exogenously added AA markedly elongated astrocytic processes. Moreover, various PLA(2) inhibitors (e.g. mepacrine and dexamethasone) prevented both the early alpha,beta-meATP-induced [H-3]-AA release and/or the associated long-term morphological changes, without affecting the astrocytic elongation induced by bFGF. Finally, the protein kinase C (PKC) inhibitor H7 fully abolished alpha,beta-meATP- but not bFGF-induced effects.4 Both alpha,beta-meATP and bFGF rapidly and transiently induced the nuclear accumulation of Fos and Jun. Both c-fos and c-jun induction by the purine analogue could be fully prevented by pretreatment with suramin. In contrast, the effects of bFGF were unaffected by this P2 receptor antagonist.5 It was concluded that alpha,beta-meATP- and bFGF-morphological differentiation of astrocytes occurs via independent transductional pathways. For the purine analogue, signalling involves a G(i)/G(o) protein-coupled P2Y-receptor which may be linked to activation of PLA(2) (involvement of an arachidonate-sensitive PKC is speculated); for bFGF, a tyrosine kinase receptor is involved. Both pathways merge on some common intracellular target, as suggested by induction of primary response genes, which in turn may regulate late response genes mediating long-term phenotypic changes of astroglial cells.6 These findings implicate P2 receptors as novel targets for the pharmacological regulation of reactive astrogliosis, which has intriguing implications in nervous system diseases characterized by degenerative events.