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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Differential crosstalk between P2X7 and arachidonic acid in activation of mitogen-activated protein kinases.
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Differential crosstalk between P2X7 and arachidonic acid in activation of mitogen-activated protein kinases.

机译：P2X7和花生四烯酸之间在激活有丝分裂原激活的蛋白激酶中的差异性串扰。

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Accumulating evidence indicates that astroglial syncytium plays key role in normal and pathological brain functions. Astrocytes both in vitro and in situ respond to extracellular adenine-based nucleotides via the activation of P2 receptors. Massive release of ATP from neurons and glial cells occurs as a result of pathological conditions of the brain leading to neuroinflammation and involving P2X7 receptors. In this study, we investigated whether P2X7 stimulation on cultured cortical astrocytes promoted a differential activation of mitogen-activated protein kinases (MAPKs), and whether the second messenger arachidonic acid (AA), which is also a key modulator of neuroinflammation, affected the P2X7-mediated MAPK phosphorylation. The results show that the synthetic P2X7 receptor agonist 2',3'-O-(4-benzoyl)benzoyl-ATP (BzATP), induced a concentration-dependent phosphorylation of MAPK ERK1/2, JNK and p38. Stimulation of ERK1/2, JNK and p38 phosphorylation was also obtained by pathophysiological levels of extracellularly applied AA. Interestingly, a robust potentiation of ERK1/2 phosphorylation was elicited by co-application of BzATP and AA, whereas no differences were observed in JNK or p38 phosphosignals. The kinases activation showed a differential dependence on the presence of extracellular Ca(2+). The potentiation of BzATP-mediated ERK1/2 phosphorylation was also observed in human embryonic kidney cells (HEK293) stably transfected with rat P2X7, but not in HEK cells expressing truncated P2X7 receptor lacking the full cytoplasmic carboxy-terminal or in those carrying the structurally related rat P2X2. AA and BzATP synergism in ERK1/2 activation was abolished by cyclo-oxygenase and lipoxygenase pathway inhibitors. The result that ERK1/2-mediated transduction pathway is synergistically modulated by ATP and AA signalling depicts possible novel pharmacological targets for interfering with pathological activation of astroglial cells.
机译：越来越多的证据表明，星形胶质合胞在正常和病理性脑功能中起关键作用。星形胶质细胞在体外和原位都通过激活P2受体对基于胞外腺嘌呤的核苷酸作出反应。 ATP从神经元和神经胶质细胞中大量释放，是由于导致神经发炎并涉及P2X7受体的大脑病理状况导致的。在这项研究中，我们调查了对培养的皮质星形胶质细胞的P2X7刺激是否促进了促分裂原活化蛋白激酶（MAPKs）的差异激活，以及第二种信使花生四烯酸（AA）（也是神经炎症的关键调节剂）是否影响了P2X7介导的MAPK磷酸化。结果表明，合成的P2X7受体激动剂2'，3'-O-（4-苯甲酰基）苯甲酰基-ATP（BzATP）诱导了MAPK ERK1 / 2，JNK和p38的浓度依赖性磷酸化。刺激ERK1 / 2，JNK和p38磷酸化还通过病理生理水平的细胞外应用AA。有趣的是，通过同时使用BzATP和AA引发ERK1 / 2磷酸化的强大增强，而在JNK或p38磷酸信号中未观察到差异。激酶激活显示出对细胞外Ca（2+）存在的差异依赖性。在用大鼠P2X7稳定转染的人胚胎肾细胞（HEK293）中也观察到BzATP介导的ERK1 / 2磷酸化的增强，但在表达缺失完整细胞质羧基末端的截短的P2X7受体的HEK细胞中或在携带结构相关的人的肾细胞中没有观察到大鼠P2X2。环氧合酶和脂氧合酶途径抑制剂消除了ERK1 / 2活化中的AA和BzATP协同作用。 ERK1 / 2介导的转导途径被ATP和AA信号协同调节的结果描述了可能干扰星形胶质细胞病理激活的新药理学靶标。

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