Ezrin regulates the expression of Mrp2/Abcc2 and Mdr1/Abcb1 along the rat small intestinal tract

被引:18
|
作者
Nakano, Takafumi [1 ]
Sekine, Shuichi [1 ]
Ito, Kousei [1 ]
Horie, Toshiharu [1 ]
机构
[1] Chiba Univ, Lab Biopharmaceut, Grad Sch Pharmaceut Sci, Chuo Ku, Chiba, Japan
关键词
ezrin; MDR1/ABCB1; MRP2/ABCC2; small intestinal tract; PROTEIN-KINASE-C; FOOD-DERIVED CARCINOGEN; ERM-FAMILY PROTEINS; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; STRUCTURAL BASIS; EFFLUX PROTEINS; TRANSPORT; MRP2; PHOSPHORYLATION;
D O I
10.1152/ajpgi.00187.2013
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Multidrug resistance-associated protein 2 (MRP2)/ATP-binding cassette protein C2 (ABCC2) and multidrug resistance protein 1 (MDR1)/ABCB1 are well-known efflux transporters located on the brush border membrane of the small intestinal epithelia, where they limit the absorption of a broad range of substrates. The expression patterns of MRP2/ABCC2 and MDR1/ABCB1 along the small intestinal tract are tightly regulated. Several reports have demonstrated the participation of ERM (ezrin/radixin/moesin) proteins in the posttranslational modulation of MRP2/ABCC2 and MDR1/ABCB1, especially with regard to their membrane localization. The present study focused on the in vivo expression profiles of MRP2/ABCC2, MDR1/ABCB1, ezrin, and phosphorylated ezrin to further elucidate the relationship between the efflux transporters and the ERM proteins. The current results showed good correlation between the phosphorylation status of ezrin and Mrp2/Abcc2 expression along the gastrointestinal tract of rats and between the expression profiles of both ezrin and Mdr1/Abcb1 in the small intestine. We also demonstrated the involvement of conventional protein kinase C isoforms in the regulation of ezrin phosphorylation. Furthermore, experiments conducted with wild-type (WT) ezrin and a T567A (Ala substituted Thr) dephosphorylated mutant showed a decrease in membrane surface-localized and total expressed MRP2/ABCC2 in T567A-expressing vs. WT ezrin-expressing Caco-2 cells. In contrast, T567A- and WT-expressing cells both showed an increase in membrane surface-localized and total expressed MDR1/ABCB1. These findings suggest that the phosphorylation status and the expression profile of ezrin differentially direct MRP2/ABCC2 and MDR1/ABCB1 expression, respectively, along the small intestinal tract.
引用
收藏
页码:G807 / G817
页数:11
相关论文
共 50 条
  • [1] Ezrin has a key role in the expression profile of MRP2 and MDR1 along intestinal tract
    Sekine, Shuichi
    Ito, Kousei
    Nakano, Takafumi
    Horie, Toshiharu
    DRUG METABOLISM REVIEWS, 2010, 42 : 312 - 313
  • [2] Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver
    Albermann, N
    Schmitz-Winnenthal, FH
    Z'graggen, K
    Volk, C
    Hoffmann, MM
    Haefeli, WE
    Weiss, J
    BIOCHEMICAL PHARMACOLOGY, 2005, 70 (06) : 949 - 958
  • [3] Individual and combined roles of CYP3A, P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) in the pharmacokinetics of docetaxel
    van Waterschoot, Robert A. B.
    Lagas, Jurjen S.
    Wagenaar, Els
    Rosing, Hilde
    Beijnen, Jos H.
    Schinkel, Alfred H.
    INTERNATIONAL JOURNAL OF CANCER, 2010, 127 (12) : 2959 - 2964
  • [4] Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in freshly isolated rat hepatocytes
    Bow, Daniel A. J.
    Perry, Jennifer L.
    Miller, David S.
    Pritchard, John B.
    Brouwer, Kim L. R.
    DRUG METABOLISM AND DISPOSITION, 2008, 36 (01) : 198 - 202
  • [5] Transport of antiepileptic drugs by the multidrug transporters PGP (ABCB1) and MRP2 (ABCC2)
    Baltes, S
    Potschka, H
    Löscher, W
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2005, 371 : R3 - R3
  • [6] Investigation of the transport of valproic acid by the multidrug transporters P-gp (ABCB1) and MRP2 (ABCC2)
    Baltes, S
    Potschka, H
    Löscher, W
    EPILEPSIA, 2005, 46 : 205 - 206
  • [7] Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology
    Vibeke Andersen
    Katrine Svenningsen
    Lina Almind Knudsen
    Axel Kornerup Hansen
    Uffe Holmskov
    Allan Stensballe
    Ulla Vogel
    World Journal of Gastroenterology, 2015, 21 (41) : 11862 - 11876
  • [8] Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology
    Andersen, Vibeke
    Svenningsen, Katrine
    Knudsen, Lina Almind
    Hansen, Axel Kornerup
    Holmskov, Uffe
    Stensballe, Allan
    Vogel, Ulla
    WORLD JOURNAL OF GASTROENTEROLOGY, 2015, 21 (41) : 11862 - 11876
  • [9] Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir
    van Waterschoot, R. A. B.
    ter Heine, R.
    Wagenaar, E.
    van der Kruijssen, C. M. M.
    Rooswinkel, R. W.
    Huitema, A. D. R.
    Beijnen, J. H.
    Schinkel, A. H.
    BRITISH JOURNAL OF PHARMACOLOGY, 2010, 160 (05) : 1224 - 1233
  • [10] Liver X receptor regulates expression of MRP2 but not that of MDR1 and BCRP in the liver
    Chisaki, Ikumi
    Kobayashi, Masaki
    Itagaki, Shirou
    Hirano, Takeshi
    Iseki, Ken
    BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2009, 1788 (11): : 2396 - 2403