Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role
Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role
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DOI：
10.1002/jnr.20850
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发表时间：
2006-06-01
影响因子：
4.2
通讯作者：
Nakata, Yoshihiro
中科院分区：
文献类型：
--
作者：
Suzuki, Tomohisa;Hide, Izumi;Nakata, Yoshihiro
小胶质细胞在大脑中执行神经保护和神经毒性功能，这取决于它们的激活状态和介质的释放。例如，在P2 X（7）受体刺激时，小胶质细胞释放少量TNF，其保护神经元，而LPS引起大量TNF释放，导致神经炎症。在这里，我们报告说，在大鼠原代培养的小胶质细胞，尼古丁增强P2 X7受体介导的TNF释放，同时抑制LPS诱导的TNF释放，但不影响TNF mRNA的表达，通过激活α 7烟碱乙酰胆碱受体（α 7 nAChRs）。在小胶质细胞中，尼古丁引起细胞内Ca 2+水平的短暂增加，这被α 7 nAChR的特异性阻断剂消除。然而，这种反应是独立的细胞外Ca 2+和阻断U 73122，磷脂酶C（PLC）的抑制剂，和xestospongin C，IP 3受体的阻滞剂。重复实验表明，在尼古丁刺激的小胶质细胞中没有检测到电流。此外，xestospongin C也可阻断尼古丁对LPS诱导的TNF释放的调节作用。在LPS刺激下，尼古丁对TNF释放的抑制与JNK和p38 MAP激酶激活的抑制有关，JNK和p38 MAP激酶激活调节TNF合成的转录后步骤。相比之下，尼古丁没有改变任何MAP激酶的激活，但增强了P2 X（7）受体激活的小胶质细胞中的Ca 2+反应。总之，小胶质细胞α 7 nAChR可能驱动涉及PLC激活和细胞内Ca 2+储存的Ca 2+释放的信号传导过程，而不是作为传统的离子通道。这种新的α 7 nAChR信号可能参与尼古丁对小胶质细胞活化的修饰，通过抑制炎症状态和加强保护功能发挥神经保护作用。(c)2006 Wiley-Liss，Inc.
Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon P2X(7) receptor stimulation, for example, microglia release small amounts of TNF, which protect neurons, whereas LPS causes massive TNF release leading to neuroinflammation. Here we report that, in rat primary cultured microglia, nicotine enhances P2X7 receptor-mediated TNF release, whilst suppressing LPS-induced TNF release but without affecting TNF mRNA expression via activation of alpha 7 nicotinic acetylcholine receptors (alpha 7 nAChRs). In microglia, nicotine elicited a transient increase in intracellular Ca2+ levels, which was abolished by specific blockers of alpha 7 nAChRs. However, this response was independent of extracellular Ca2+ and blocked by U73122, an inhibitor of phospholipase C (PLC), and xestospongin C, a blocker of the IP3 receptor. Repeated experiments showed that currents were not detected in nicotine-stimulated microglia. Moreover, nicotine modulation of LPS-induced TNF release was also blocked by xestospongin C. Upon LPS stimulation, inhibition of TNF release by nicotine was associated with the suppression of JNK and p38 MAP kinase activation, which regulate the post-transcriptional steps of TNF synthesis. In contrast, nicotine did not alter any MAP kinase activation, but enhanced Ca2+ response in P2X(7) receptor-activated microglia. In conclusion, microglial alpha 7 nAChRs might drive a signaling process involving the activation of PLC and Ca2+ release from intracellular Ca2+ stores, rather than function as conventional ion channels. This novel alpha 7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function. (c) 2006 Wiley-Liss, Inc.