Internalization of basic fibroblast growth factor at the mouse blood-brain barrier involves perlecan, a heparan sulfate proteoglycan

被引:47
|
作者
Deguchi, Y
Okutsu, H
Okura, T
Yamada, S
Kimura, R
Yuge, T
Furukawa, A
Morimoto, K
Tachikawa, M
Ohtsuki, S
Hosoya, K
Terasaki, T
机构
[1] Teikyo Univ, Sch Pharmaceut Sci, Dept Drug Disposit & Pharmacokinet, Sagamiko, Kanagawa 1990195, Japan
[2] Hokkaido Coll Pharm, Dept Biopharmaceut, Otaru, Hokkaido, Japan
[3] Univ Shizuoka, Sch Pharmaceut Sci, Dept Biopharm, Shizuoka 422, Japan
[4] Kaken Pharmaceut Co Ltd, FGF Prod Team, Tokyo, Japan
[5] Tohoku Univ, Grad Sch Pharmaceut Sci, Japan Sci & Technol Corp, CREST, Sendai, Miyagi 980, Japan
[6] Tohoku Univ, Grad Sch Pharmaceut Sci, Dept Mol Biopharm & Genet, Sendai, Miyagi 980, Japan
关键词
basic fibroblast growth factor; blood-brain barrier; FGFRs; heparan sulfate proteoglycans-mediated endocytosis; perlecan;
D O I
10.1046/j.1471-4159.2002.01129.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In this study, the internalization mechanism of basic fibroblast growth factor (bFGF) at the blood-brain barrier (BBB) was investigated using a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4 cells) as an in vitro model of the BBB and the corresponding receptor was identified using immunohistochemical analysis. The heparin-resistant binding of [(125) I]bFGF to TM-BBB4 cells was found to be time-, temperature-, osmolarity- and concentration-dependent. Kinetic analysis of the cell-surface binding of [(125) I]bFGF to TM-BBB4 cells revealed saturable binding with a half-saturation constant of 76 +/- 24 nm and a maximal binding capacity of 183 +/- 17 pmol/mg protein. The heparin-resistant binding of [(125) I]bFGF to TM-BBB4 was significantly inhibited by a cationic polypeptide poly-L-lysine (300 mum), and compounds which contain a sulfate moiety, e.g. heparin and chondroitin sulfate-B (each 10 mug/mL). Moreover, the heparin-resistant binding of [(125) I]bFGF in TM-BBB4 cells was significantly reduced by 50% following treatment with sodium chlorate, suggesting the loss of perlecan (a core protein of heparan sulfate proteoglycan, HSPG) from the extracellular matrix of the cells. This type of binding is consistent with the involvement HSPG-mediated endocytosis. RT-PCR analysis revealed that HSPG mRNA and FGFR1 and FGFR2 (tyrosine-kinase receptors for bFGF) mRNA are expressed in TM-BBB4 cells. Moreover, immunohistochemical analysis demonstrated that perlecan is expressed on the abluminal membrane of the mouse brain capillary. These results suggest that bFGF is internalized via HSPG, which is expressed on the abluminal membrane of the BBB. HSPG at the BBB may play a role in maintaining the BBB function due to acceptance of the bFGF secreted from astrocytes.
引用
收藏
页码:381 / 389
页数:9
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