Akt activation is involved in P2Y12 receptor-mediated chemotaxis of microglia
Akt activation is involved in P2Y12 receptor-mediated chemotaxis of microglia
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DOI：
10.1002/jnr.21610
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发表时间：
2008-05-15
影响因子：
4.2
通讯作者：
Ohsawa, Keiko
中科院分区：
文献类型：
--
作者：
Irino, Yasuhiro;Nakamura, Yasuko;Ohsawa, Keiko
小胶质细胞在中枢神经系统（CNS）中发挥着多种重要作用，其中一种作用是在神经损伤后发生形态学改变并迁移到损伤区域。我们以前报道过ATP/ADP通过Gi/o偶联的P2 Y12受体促进小胶质细胞的趋化性;然而，P2 Y12受体介导的小胶质细胞趋化性的细胞内信号转导机制尚未完全了解。在这项研究中，我们研究了磷脂酶C（PLC）和钙信号在ADP诱导的小胶质细胞趋化性的作用。PLC抑制剂U 73122显著抑制细胞的趋化性，并完全阻断ADP诱导的细胞内钙反应，钙螯合剂BAPTA-AM抑制细胞的趋化性。这些结果表明，ADP诱导的小胶质细胞趋化性是由PLC介导的钙通道调节。ADP刺激可诱导小胶质细胞Akt磷酸化，P2 Y12受体拮抗剂AR-C69931 MX可抑制Akt磷酸化。Akt磷酸化被U 73122和BAPTA-AM以及磷脂酰肌醇3-激酶（PI 3 K）抑制剂渥曼青霉素阻断，并且Akt活化的抑制导致趋化性失败。这些结果表明，Akt的激活依赖于PI 3 K途径和PLC介导的细胞内钙的增加，并表明Akt的激活参与ADP诱导的小胶质细胞趋化性。(c)2008 Wiley-Liss，Inc.
Microglia play a variety of significant roles in the central nervous system (CNS), and in one of those roles they undergo morphological change in response to neural injury and migrate to the injured region. We previously reported that ATP/ADP promotes microglial chemotaxis via the Gi/o-coupled P2Y12 receptor; however, the intracellular signaling underlying P2Y12-receptor-mediated microglial chemotaxis is not fully understood. In this study, we examined the role of phospholipase C (PLC) and calcium signaling in ADP-induced microglial chemotaxis. A PLC inhibitor, U73122, significantly suppressed the chemotaxis and completely blocked the ADP-evoked intracellular calcium response, and a calcium chelator, BAPTA-AM, inhibited the chemotaxis. These results indicate that ADP-induced microglial chemotaxis is regulated by a PLC-mediated calcium pathway. ADP stimulation induced Akt phosphorylation in microglia, and the phosphorylation was inhibited by a P2Y12 receptor antagonist, AR-C69931MX. The Akt phosphorylation was blocked by U73122 and BAPTA-AM as well as by a phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, and inhibition of the Akt activation resulted in failure of chemotaxis. These results indicate that Akt activation is dependent on the PI3K pathway and a PLC-mediated increase in intracellular calcium and suggest that Akt activation is involved in ADP-induced microglial chemotaxis. (c) 2008 Wiley-Liss, Inc.