Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration
Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration
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DOI：
10.1016/j.bbamcr.2016.05.018
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发表时间：
2016-09-01
影响因子：
5.1
通讯作者：
Leyton, Lisette
中科院分区：
文献类型：
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作者：
Alvarez, Alvaro;Lagos-Cabre, Raul;Leyton, Lisette
我们以前的报告表明，配体诱导的α(V)β(3)整合素和Syndecan-4的参与增加了星形胶质细胞局部黏附的形成和迁移。此外，连接的整合素通过未知的机制启动ATP释放，激活P2X7受体(P2X7R)，并摄取Ca~(2+)促进细胞黏附。然而，星形胶质细胞的迁移是否需要P2X7R的激活和ATP的释放，以及α(V)β(3)整合素和Syndecan-4受体是否通过ATP与P2X7R进行通讯仍不清楚。在这里，细胞被Thy-1刺激，Thy-1是一种报道的α(V)β(3)整合素和Syndecan-4配体。结果表明，Thy-1与整合素结合后释放ATP，需要磷脂酰肌醇-3-激酶(PI3K)、磷脂酶-C-γ(PLC-γ)和三磷酸肌醇(IP3)受体(IP3R)参与。IP3R激活导致细胞内钙离子、半通道(连接蛋白-43和连接蛋白-1)开放和ATP释放增加。此外，沉默P2X7R或添加半隧道阻滞剂可阻止Thy-I诱导的星形胶质细胞迁移。最后，缺乏整合素结合部位的Thy-1不刺激ATP的释放，而在Syndecan-4结合区突变的Thy-1增加了ATP的释放，尽管幅度较小，而且与野生型Thy-1相比具有延迟的动力学效应。因此，在α(V)β(3)整合素-PI3K-PLCγ-IP3R通路下游激活的半通道负责Thy-1诱导、半通道介导和Syndecan-4调节的ATP释放，从而反式激活P2X7Rs诱导钙内流。这些发现揭示了半脑管通过整合素介导的ATP释放诱导的P2X7R反式激活来调节星形胶质细胞迁移的迄今未被认识的作用。(C)2016爱思唯尔B.V.保留所有权利。
Our previous reports indicate that ligand-induced alpha(v)beta(3) integrin and Syndecan-4 engagement increases focal adhesion formation and migration of astrocytes. Additionally, ligated integrins trigger ATP release through unknown mechanisms, activating P2X7 receptors (P2X7R), and the uptake of Ca2+ to promote cell adhesion. However, whether the activation of P2X7R and ATP release are required for astrocyte migration and whether alpha(v)beta(3) integrin and Syndecan-4 receptors communicate with P2X7R via ATP remains unknown. Here, cells were stimulated with Thy-1, a reported alpha(v)beta(3) integrin and Syndecan-4 ligand. Results obtained indicate that ATP was released by Thy-1 upon integrin engagement and required the participation of phosphatidylinositol-3-kinase (PI3K), phospholipase-C gamma (PLC-gamma) and inositol trisphosphate (IP3) receptors (IP3R). IP3R activation leads to increased intracellular Ca2+, hemichannel (Connexin-43 and Pannexin-1) opening, and ATP release. Moreover, silencing of the P2X7R or addition of hemichannel blockers precluded Thy-I-induced astrocyte migration. Finally, Thy-1 lacking the integrin-binding site did not stimulate ATP release, whereas Thy-1 mutated in the Syndecan-4-binding domain increased ATP release, albeit to a lesser extent and with delayed kinetics compared to wild-type Thy-1. Thus, hemichannels activated downstream of an alpha(v)beta(3) integrin-PI3K-PLC gamma-IP3R pathway are responsible for Thy-1-induced, hemichannel-mediated and Syndecan-4-modulated ATP release that transactivates P2X7Rs to induce Ca2+ entry. These findings uncover a hitherto unrecognized role for hemichannels in the regulation of astrocyte migration via P2X7R transactivation induced by integrin-mediated ATP release. (C) 2016 Elsevier B.V. All rights reserved.