Reduced cAMP, Akt activation and p65-c-Rel dimerization: mechanisms involved in the protective effects of mGluR3 agonists in cultured astrocytes.
Reduced cAMP, Akt activation and p65-c-Rel dimerization: mechanisms involved in the protective effects of mGluR3 agonists in cultured astrocytes.
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DOI：
10.1371/journal.pone.0022235
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lasaga M
中科院分区：
文献类型：
--
作者：
Durand D;Carniglia L;Caruso C;Lasaga M
近几十年来，星形胶质细胞已成为维持中枢神经系统正常功能的关键部分。星形胶质细胞功能的任何损伤最终都可能导致大脑中的广泛性障碍，因此与预防星形胶质细胞死亡相关的药理学靶点实际上是有希望的。代谢型谷氨酸受体亚型3（mGluR 3）存在于星形胶质细胞中，其活化发挥神经保护作用。事实上，我们以前已经证明，mGluR 3选择性激动剂防止一氧化氮（NO）诱导的星形胶质细胞死亡。然而，负责该细胞保护性质的机制仍有待研究。尽管广泛报道了mGluR 3激活对腺苷酸环化酶的抑制作用，但mGluR 3激动剂作用中cAMP水平降低的参与以及cAMP降低与mGluR 3激活的下游途径之间的关联仍然被忽视。因此，我们研究了细胞内信号转导介导的抗凋亡作用的mGluR 3在培养的大鼠星形胶质细胞暴露于NO。在目前的工作中，我们表明，细胞保护作用的mGluR 3激动剂（LY 379268和LY 404039）需要细胞内cAMP水平的降低和Akt的激活，通过MTT和TUNEL技术进行评估。此外，二丁酰-cAMP损害由LY 404039诱导的Akt磷酸化，表明mGluR 3降低的cAMP水平与PI 3 K/Akt通路活化之间的关系。我们还通过免疫共沉淀和蛋白质印迹证明，mGluR 3激动剂不仅诱导NF-κB家族成员p65和c-Rel之间的本身与存活相关的相互作用，而且还阻止由NO引起的p65-c-Rel二聚体水平的降低，表明p65-c-Rel可能具有抗凋亡作用。这些结果提示，mGluR 3激动剂可能通过调节cAMP/Akt/p65-c-Rel通路发挥其保护作用。我们的研究结果拓宽了有关mGluR 3的作用机制的知识，mGluR 3是治疗神经退行性疾病的潜在靶点，其中NO的病理生理作用已经确立。
In recent decades, astrocytes have emerged as key pieces in the maintenance of normal functioning of the central nervous system. Any impairment in astroglial function can ultimately lead to generalized disturbance in the brain, thus pharmacological targets associated with prevention of astrocyte death are actually promising. Subtype 3 of metabotropic glutamate receptors (mGluR3) is present in astrocytes, its activation exerting neuroprotective roles. In fact, we have previously demonstrated that mGluR3 selective agonists prevent nitric oxide (NO)-induced astrocyte death. However, mechanisms responsible for that cytoprotective property are still subject to study. Although inhibition of adenylyl cyclase by mGluR3 activation was extensively reported, the involvement of reduced cAMP levels in the effects of mGluR3 agonists and the association between cAMP decrease and the downstream pathways activated by mGluR3 remain neglected. Thus, we studied intracellular signaling mediating anti-apoptotic actions of mGluR3 in cultured rat astrocytes exposed to NO. In the present work, we showed that the cytoprotective effect of mGluR3 agonists (LY379268 and LY404039) requires both the reduction of intracellular cAMP levels and activation of Akt, as assessed by MTT and TUNEL techniques. Moreover, dibutyryl-cAMP impairs Akt phosphorylation induced by LY404039, indicating a relationship between mGluR3-reduced cAMP levels and PI3K/Akt pathway activation. We also demonstrated, by co-immunoprecipitation followed by western-blot, that the mGluR3 agonists not only induce per se survival-linked interaction between members of the NF-κB family p65 and c-Rel, but also impede reduction of levels of p65-c-Rel dimers caused by NO, suggesting a possible anti-apoptotic role for p65-c-Rel. All together, these data suggest that mGluR3 agonists may regulate cAMP/Akt/p65-c-Rel pathway, which would contribute to the protective effect of mGluR3 against NO challenge in astrocytes. Our results widen the knowledge about mechanisms of action of mGluR3, potential targets for the treatment of neurodegenerative disorders where a pathophysiological role for NO has been established.
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影响因子：
4.7
作者：
Durand, Daniela;Caruso, Carla;Lasaga, Mercedes
通讯作者：
Lasaga, Mercedes
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2.9
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