P-glycoprotein in blood-brain barrier endothelial cells:: interaction and oligomerization with caveolins

被引:89
作者
Jodoin, J
Demeule, M
Fenart, L
Cecchelli, R
Farmer, S
Linton, KJ
Higgins, CF
Béliveau, R
机构
[1] Univ Quebec, Hop St Justine, Mol Med Lab, Ctr Cancerol Charles Bruneau, Montreal, PQ H3C 3P8, Canada
[2] Univ Sci & Tech Lille Flandres Artois, Lab Mixte Inst Pasteur Lille, Lens, France
[3] Hammersmith Hosp, MRC, Ctr Clin Sci, London, England
关键词
blood-brain barrier; brain; caveolae; caveolin; endothelial cell; P-glycoprotein;
D O I
10.1046/j.1471-4159.2003.02081.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
P-glycoprotein (P-gp), an adenosine triphosphate (ATP)-binding cassette transporter which acts as a drug efflux pump, is highly expressed at the blood-brain barrier (BBB) where it plays an important role in brain protection. Recently, P-gp has been reported to be located in the caveolae of multidrug-resistant cells. In this study, we investigated the localization and the activity of P-gp in the caveolae of endothelial cells of the BBB. We used an in vitro model of the BBB which is formed by co-culture of bovine brain capillary endothelial cells (BBCEC) with astrocytes. Caveolar microdomains isolated from BBCEC are enriched in P-gp, cholesterol, caveolin-1, and caveolin-2. Moreover, P-gp interacts with caveolin-1 and caveolin-2; together, they form a high molecular mass complex. P-gp in isolated caveolae is able to bind its substrates, and the caveolae-disrupting agents filipin III and nystatin decrease P-gp transport activity. In addition, mutations in the caveolin-binding motif present in P-gp reduced the interaction of P-gp with caveolin-1 and increased the transport activity of P-gp. Thus, P-gp expressed at the BBB is mainly localized in caveolae and its activity may be modulated by interaction with caveolin-1.
引用
收藏
页码:1010 / 1023
页数:14
相关论文
共 69 条
[51]   OLIGOMERIC STRUCTURE OF CAVEOLIN - IMPLICATIONS FOR CAVEOLAE MEMBRANE ORGANIZATION [J].
SARGIACOMO, M ;
SCHERER, PE ;
TANG, ZL ;
KUBLER, E ;
SONG, KS ;
SANDERS, MC ;
LISANTI, MP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9407-9411
[52]   SIGNAL-TRANSDUCING MOLECULES AND GLYCOSYL-PHOSPHATIDYLINOSITOL-LINKED PROTEINS FORM A CAVEOLIN-RICH INSOLUBLE COMPLEX IN MDCK CELLS [J].
SARGIACOMO, M ;
SUDOL, M ;
TANG, ZL ;
LISANTI, MP .
JOURNAL OF CELL BIOLOGY, 1993, 122 (04) :789-807
[53]   P-glycoprotein, a gatekeeper in the blood-brain barrier [J].
Schinkel, AH .
ADVANCED DRUG DELIVERY REVIEWS, 1999, 36 (2-3) :179-194
[54]   DISRUPTION OF THE MOUSE MDR1A P-GLYCOPROTEIN GENE LEADS TO A DEFICIENCY IN THE BLOOD-BRAIN-BARRIER AND TO INCREASED SENSITIVITY TO DRUGS [J].
SCHINKEL, AH ;
SMIT, JJM ;
VANTELLINGEN, O ;
BEIJNEN, JH ;
WAGENAAR, E ;
VANDEEMTER, L ;
MOL, CAAM ;
VANDERVALK, MA ;
ROBANUSMAANDAG, EC ;
TERIELE, HPJ ;
BERNS, AJM ;
BORST, P .
CELL, 1994, 77 (04) :491-502
[55]  
SCHINKEL AH, 1991, CANCER RES, V51, P2628
[56]  
Schlaepfer R, 2000, MANAG FOR ECOSYST, V1, P1
[57]   FILIPIN-SENSITIVE CAVEOLAE-MEDIATED TRANSPORT IN ENDOTHELIUM - REDUCED TRANSCYTOSIS, SCAVENGER ENDOCYTOSIS, AND CAPILLARY-PERMEABILITY OF SELECT MACROMOLECULES [J].
SCHNITZER, JE ;
OH, P ;
PINNEY, E ;
ALLARD, J .
JOURNAL OF CELL BIOLOGY, 1994, 127 (05) :1217-1232
[58]   Role of plasmalemmal caveolae in signal transduction [J].
Shaul, PW ;
Anderson, RGW .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1998, 275 (05) :L843-L851
[59]   Lipid rafts and signal transduction [J].
Simons, K ;
Toomre, D .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2000, 1 (01) :31-39
[60]   Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains - Detergent-free purification of caveolae membranes [J].
Song, KS ;
Li, SW ;
Okamoto, T ;
Quilliam, LA ;
Sargiacomo, M ;
Lisanti, MP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (16) :9690-9697