Internalization of PrP106-126 by the formyl-peptide-receptor-like-1 in glial cells
Internalization of PrP106-126 by the formyl-peptide-receptor-like-1 in glial cells
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DOI：
10.1111/j.1471-4159.2006.04351.x
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发表时间：
2007-05-01
影响因子：
4.7
通讯作者：
Lucius, Ralph
中科院分区：
文献类型：
--
作者：
Brandenburg, Lars-Ove;Koch, Thomas;Lucius, Ralph
最近的研究表明，甲酰基肽受体样1（FPRL 1）在宿主防御机制和神经退行性疾病的炎症反应中发挥着重要作用。此外，它可能参与朊病毒疾病的促炎过程。然而，人们对PrP 106 -126诱导的受体内吞作用的诱导和调节知之甚少。因此，我们分析了PrP 106 -126是否通过FPRL 1增加磷脂酶D（PLD）的活性，FPRL 1是一种参与神经胶质细胞分泌、内吞和受体信号传导调节的酶。使用转磷脂酰化测定法测定PLD活性，并通过荧光显微镜评估PrP 106 -126和FPRL 1的内化，并通过ELISA定量。我们可以证明PLD在星形胶质细胞和小胶质细胞中都被PrP 106 -126激活，而且PrP 106 -126在星形胶质细胞和小胶质细胞中通过FPRL 1快速内化。通过细胞外信号调节激酶1/2磷酸化和cAMP水平测量的受体活性的测定证实了PrP 106 -126诱导的FPRL 1活化。FPRL 1介导的PrP 106 -126摄取被受体拮抗剂鹅去氧胆酸阻断。这些研究表明，参与FPRL 1介导的细胞信号转导PrP 106 -126-内吞作用，并可能允许开发干扰朊病毒摄取和/或PLD功能的治疗剂，使用PLD或FPRL 1作为可能的药物靶点。
Recent studies suggest that the formyl-peptide-receptor-like-1 (FPRL1) plays an essential role in inflammatory responses in the host defence mechanisms and neurodegenerative disorders. Furthermore, it may be involved in proinflammatory processes of prion diseases. However, little is known about the induction and regulation of PrP106-126-induced receptor endocytosis. We have thus analysed whether PrP106-126 increases the activity of phospholipase D (PLD) via FPRL1, an enzyme involved in the regulation of the secretion, endocytosis and receptor signalling, in glial cells. PLD activity was determined using a transphosphatidylation assay and the internalization of PrP106-126, and FPRL1 was assessed by fluorescence microscopy and quantified by ELISA. We could show that PLD is activated by PrP106-126 both in astrocytes and microglia, and moreover that PrP106-126 is rapidly internalized via FPRL1 in astrocytes and microglia cells. The determination of receptor activity by extracellular signal-regulated kinases 1/2 phosphorylation and cAMP level measurement verified the PrP106-126-induced activation of FPRL1. FPRL1-mediated PrP106-126 uptake was blocked by the receptor antagonist chenodeoxycholic acid. These studies indicate the involvement of FPRL1-mediated cellular signalling in PrP106-126-endocytosis and may allow the development of therapeutic agents interfering with prion uptake and/or PLD function, using either PLD or the FPRL1 as a possible pharmaceutical target.