Internalization of PrP(106-126) by the formyl-peptide-receptor-like-1 in glial cells.

摘要

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 PrP(106-126)-induced receptor endocytosis. We have thus analysed whether PrP(106-126) 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 PrP(106-126), and FPRL1 was assessed by fluorescence microscopy and quantified by ELISA. We could show that PLD is activated by PrP(106-126) both in astrocytes and microglia, and moreover that PrP(106-126) 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 PrP(106-126)-induced activation of FPRL1. FPRL1-mediated PrP(106-126) uptake was blocked by the receptor antagonist chenodeoxycholic acid. These studies indicate the involvement of FPRL1-mediated cellular signalling in PrP(106-126)-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.