PDF herunterladen
Semin Liver Dis 2000; Volume 20(Number 03): 339-352
DOI: 10.1055/s-2000-9388
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Intracellular Trafficking and Regulation of Canalicular ATP-Binding Cassette Transporters

HELMUT. KIPP, IRWIN. M. ARIAS
  • From the Tufts University School of Medicine, Department of Physiology, Boston, Massachusetts
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
31. Dezember 2000 (online)

    Lizenzen und Reprints

ABSTRACT

The bile canaliculus contains at least four ATP-binding cassette (ABC) proteins responsible for ATP-dependent transport of bile acids (spgp), nonbile acid organic anions (mrp2), organic cations (mdr1), and phosphatidylcholine (mdr2). Other ABC transporters (including mrp3) have also been partially localized to the canaliculus; however, their function has not been fully delineated. The specific amount and function of spgp and mrp2 in the canalicular membrane increases in response to taurocholate and cAMP. The mechanism involves increased recruitment of spgp and mrp2 from Golgi to the canalicular membrane by a microtubular and PI3 kinase-dependent vesicular trafficking system. Because the effects of taurocholate and cAMP summate, two distinct pathways are proposed. Mdr family members traffic either directly to the apical plasma membrane or, in the case of spgp, through a separate intracellular pool(s); in either case, there is no direct evidence for transcytosis of ABC transporters from Golgi to basolateral plasma membrane and subsequently to the canalicular plasma membrane. Direct transfer from Golgi to apical membrane was demonstrated by in vivo pulse labeling, in vitro membrane localization, and on-line video microscopy in WIFB9 cells that were stably transfected with mdr1-GFP. A critical role for 3′-phosphoinositide products of PI3 kinase was demonstrated in the intracellular trafficking of canalicular ABC transporters and for optimal transporter activity within the canalicular membrane. These studies suggest that many intracellular components, including ATP, Ca3 +, numerous GTPases, microtubules, cytoplasmic motors, and other unknown factors, are required for physiologic regulation of ABC transporter traffic from Golgi to the canalicular membrane. Defects in this complex system are postulated to produce an ``intrahepatic traffic jam'' that results in defective ABC transporter function in the canalicular membrane and, consequently, in cholestasis.

KEYWORD

hepatocyte - bile canaliculus - ATP-binding cassette transporter - trafficking

REFERENCES

  • 1 Nishida T, Gatmaitan Z, Che M. Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system.  Proc Natl Acad Sci USA . 1991;  88 6590-6594
    CrossrefPubMedGoogle Scholar
  • 2 Nishida T, Hardenbrook C, Gatmaitan Z. ATP-dependent organic anion transport system in normal and TR- rat liver canalicular membranes.  Am J Physiol . 1992;  262 G629-G635
    PubMedGoogle Scholar
  • 3 Stieger B, O'Neill B, Meier P J. ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles.  Biochem J . 1992;  284 67-74
    PubMedGoogle Scholar
  • 4 Gatmaitan Z C, Arias I M. ATP-dependent transport systems in the canalicular membrane of the hepatocyte.  Physiol Rev . 1995;  75 261-275
    PubMedGoogle Scholar
  • 5 Higgins C F. ABC transporters: From microorganisms to man.  Annu Rev Cell Biol . 1992;  8 67-113
    CrossrefPubMedGoogle Scholar
  • 6 Kamimoto Y, Gatmaitan Z, Hsu J. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles.  J Biol Chem . 1989;  264 11693-11698
    PubMedGoogle Scholar
  • 7 Ruetz S, Gros P. Phosphatidylcholine translocase: A physiological role for the mdr2 gene.  Cell . 1994;  77 1071-1081
    CrossrefPubMedGoogle Scholar
  • 8 Nies A T, Gatmaitan Z, Arias I M. ATP-dependent phosphatidylcholine translocation in rat liver canalicular plasma membrane vesicles.  J Lipid Res . 1996;  37 1125-1136
    PubMedGoogle Scholar
  • 9 Gerloff T, Stieger B, Hagenbuch B. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem . 1998;  273 10046-10050
    CrossrefPubMedGoogle Scholar
  • 10 Büchler M, König J, Brom M. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats.  J Biol Chem . 1996;  271 15091-15098
    CrossrefPubMedGoogle Scholar
  • 11 Gatmaitan Z C, Nies A T, Arias I M. Regulation and translocation of ATP-dependent apical membrane proteins in rat liver.  Am J Physiol . 1997;  272 G1041-G1049
    PubMedGoogle Scholar
  • 12 Misra S, Ujhazy P, Gatmaitan Z. The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver.  J Biol Chem . 1998;  273 26638-26644
    CrossrefPubMedGoogle Scholar
  • 13 Misra S, Ujhazy P, Varticovski L. Phosphoinositide 3-kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles.  Proc Natl Acad Sci USA . 1999;  96 5814-5819
    CrossrefPubMedGoogle Scholar
  • 14 Paumgartner G, Herz R, Sauter K. Taurocholate excretion and bile formation in the isolated perfused rat liver. An in vitro-in vivo comparison.  Naunyn Schmiedebergs Arch Pharmacol . 1974;  285 165-174
    CrossrefPubMedGoogle Scholar
  • 15 Lowe P J, Barnwell S G, Coleman R. Rapid kinetic analysis of the bile-salt-dependent secretion of phospholipid, cholesterol and a plasma-membrane enzyme into bile.  Biochem J . 1984;  222 631-637
    PubMedGoogle Scholar
  • 16 Barnwell S G, Godfrey P P, Lowe P J. Biliary protein output by isolated perfused rat livers.  Effects of bile salts. Biochem J . 1983;  210 549-557
    PubMedGoogle Scholar
  • 17 LeSage G D, Robertson W E, Baumgart M A. Bile acid-dependent vesicular transport of lysosomal enzymes into bile in the rat.  Gastroenterology . 1993;  105 889-900
    PubMedGoogle Scholar
  • 18 Crawford J M, Berken C A, Gollan J L. Role of the hepatocyte microtubular system in the excretion of bile salts and biliary lipid: Implications for intracellular vesicular transport.  J Lipid Res . 1988;  29 144-156
    PubMedGoogle Scholar
  • 19 Hayakawa T, Bruck R, Ng O C. DBcAMP stimulates vesicle transport and HRP excretion in isolated perfused rat liver.  Am J Physiol . 1990;  259 G727-G735
    PubMedGoogle Scholar
  • 20 Davidson H W, McGovan C H, Balch W E. Evidence for the regulation of exocytic transport by protein phosphorylation.  J Cell Biol . 1992;  116 1343-1355
    CrossrefPubMedGoogle Scholar
  • 21 Richter-Landsberg C, Jastorff B. In vitro phosphorylation of microtubule-associated protein 2: Differential effects of cyclic AMP analogues.  J Neurochem . 1985;  45 1218-1222
    PubMedGoogle Scholar
  • 22 Whitman M, Kaplan D R, Schaffhausen B. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation.  Nature . 1985;  315 239-242
    CrossrefPubMedGoogle Scholar
  • 23 Fruman D A, Meyers R E, Cantley L C. Phosphoinositide kinases.  Annu Rev Biochem . 1998;  67 481-507
    CrossrefPubMedGoogle Scholar
  • 24 Toker A, Cantley L C. Signalling through the lipid products of phosphoinositide-3-OH kinase.  Nature . 1997;  387 673-676
    CrossrefPubMedGoogle Scholar
  • 25 Domin J, Waterfield M D. Using structure to define the function of phosphoinositide 3-kinase family members.  FEBS Lett . 1997;  410 91-95
    CrossrefPubMedGoogle Scholar
  • 26 Arcaro A, Wymann M P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: The role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses.  Biochem J . 1993;  296 297-301
    PubMedGoogle Scholar
  • 27 Folli F, Alvaro D, Gigliozzi A. Regulation of endocytic-transcytotic pathways and bile secretion by phosphatidylinositol 3-kinase in rats.  Gastroenterology . 1997;  113 954-965
    PubMedGoogle Scholar
  • 28 Hems R, Ross B D, Berry M N. Gluconeogenesis in the perfused rat liver.  Biochem J . 1966;  101 284-292
    PubMedGoogle Scholar
  • 29 Janmey P A, Cunningham C C, Stossel T P. U.S Patent 5,846,743
    Google Scholar
  • 30 Hartwig J H, Bokoch G M, Carpenter C L. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets.  Cell . 1995;  82 643-653
    CrossrefPubMedGoogle Scholar
  • 31 Lu P J, Shieh W R, Rhee S G. Lipid products of phosphoinositide 3-kinase bind human profilin with high affinity.  Biochemistry . 1996;  35 14027-14034
    CrossrefPubMedGoogle Scholar
  • 32 Doige C A, Yu X, Sharom F J. The effects of lipids and detergents on ATPase-active P-glycoprotein.  Biochim Biophys Acta . 1993;  1146 65-72
    PubMedGoogle Scholar
  • 33 Sharom F J. The P-glycoprotein multidrug transporter: Interactions with membrane lipids, and their modulation of activity.  Biochem Soc Trans . 1997;  25 1088-1096
    PubMedGoogle Scholar
  • 34 Shyng S L, Nichols C G. Membrane phospholipid control of nucleotide sensitivity of KATP channels.  Science . 1998;  282 1138-1141
    CrossrefPubMedGoogle Scholar
  • 35 Baukrowitz T, Schulte U, Oliver D. PIP2 and PIP as determinants for ATP inhibition of KATP channels.  Science . 1998;  282 1141-1144
    CrossrefPubMedGoogle Scholar
  • 36 Bartles J R, Feracci H M, Stieger B. Biogenesis of the rat hepatocyte plasma membrane in vivo: Comparison of the pathways taken by apical and basolateral proteins using subcellular fractionation.  J Cell Biol . 1987;  105 1241-1251
    CrossrefPubMedGoogle Scholar
  • 37 Schell M J, Maurice M, Stieger B. 5′Nucleotidase is sorted to the apical domain of hepatocytes via an indirect route.  J Cell Biol . 1992;  119 1173-1182
    CrossrefPubMedGoogle Scholar
  • 38 Bartles J R, Hubbard A L. Plasma membrane protein sorting in epithelial cells: Do secretory pathways hold the key?.  Trends Biochem Sci . 1988;  13 181-184
    CrossrefPubMedGoogle Scholar
  • 39 Roelofsen H, Soroka C J, Keppler D. Cyclic AMP stimulates sorting of the canalicular organic anion transporter (Mrp2/cMoat) to the apical domain in hepatocyte couplets.  J Cell Sci . 1998;  111 1137-1145
    PubMedGoogle Scholar
  • 40 Kipp H, Arias I M. Newly synthesized canalicular ABC-transporters are directly targeted from Golgi to the hepatocyte apical domain in rat liver.  J Biol Chem . 2000;  275 15917-15925
    CrossrefPubMedGoogle Scholar
  • 41 Soroka C J, Pate M K, Boyer J L. Canalicular export pumps traffic with polymeric immunoglobulin A receptor on the same microtubule-associated vesicle in rat liver.  J Biol Chem . 1999;  274 26416-26424
    CrossrefPubMedGoogle Scholar
  • 42 Ihrke G, Martin G V, Shanks M R. Apical plasma membrane proteins and endolyn-78 travel through a subapical compartment in polarized WIF-B hepatocytes.  J Cell Biol . 1998;  141 115-133
    CrossrefPubMedGoogle Scholar
  • 43 Bomsel M, Prydz K, Parton R G. Endocytosis in filter-grown Madin-Darby canine kidney cells.  J Cell Biol . 1989;  109 3243-3258
    CrossrefPubMedGoogle Scholar
  • 44 Hughson E J, Hopkins C R. Endocytic pathways in polarized Caco-2 cells: Identification of an endosomal compartment accessible from both apical and basolateral surfaces.  J Cell Biol . 1990;  110 337-348
    CrossrefPubMedGoogle Scholar
  • 45 Apodaca G, Katz L A, Mostov K E. Receptor-mediated transcytosis of IgA in MDCK cells is via apical recycling endosomes.  J Cell Biol . 1994;  125 67-86
    CrossrefPubMedGoogle Scholar
  • 46 Barroso M, Sztul E S. Basolateral to apical transcytosis in polarized cells is indirect and involves BFA and trimeric G protein sensitive passage through the apical endosome.  J Cell Biol . 1994;  124 83-100
    CrossrefPubMedGoogle Scholar
  • 47 Sai Y, Nies A T, Arias I M. Bile acid secretion and direct targeting of mdr1-green fluorescent protein from golgi to the canalicular membrane in polarized WIF-B cells.  J Cell Sci . 1999;  112 4535-4545
    PubMedGoogle Scholar
  • 48 Ihrke G, Neufeld E B, Meads T. WIF-B cells: An in vitro model for studies of hepatocyte polarity.  J Cell Biol . 1993;  123 1761-1775
    CrossrefPubMedGoogle Scholar
  • 49 Shanks M R, Cassio D, Lecoq O. An improved polarized rat hepatoma hybrid cell line. Generation and comparison with its hepatoma relatives and hepatocytes in vivo.  J Cell Sci . 1994;  107 813-825
    PubMedGoogle Scholar
  • 50 Nies A T, Cantz T, Brom M. Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B.  Hepatology . 1998;  28 1332-1340
    CrossrefPubMedGoogle Scholar
  • 51 Presley J F, Cole N B, Schroer T A. ER-to-Golgi transport visualized in living cells.  Nature . 1997;  389 81-85
    CrossrefPubMedGoogle Scholar
  • 52 Toomre D, Keller P, White J. Dual-color visualization of trans-Golgi network to plasma membrane traffic along microtubules in living cells.  J Cell Sci . 1999;  112 21-33
    PubMedGoogle Scholar
  • 53 Nakata T, Terada S, Hirokawa N. Visualization of the dynamics of synaptic vesicle and plasma membrane proteins in living axons.  J Cell Biol . 1998;  140 659-674
    CrossrefPubMedGoogle Scholar
  • 54 Hirschberg K, Miller C M, Ellenberg J. Kinetic analysis of secretory protein traffic and characterization of golgi to plasma membrane transport intermediates in living cells.  J Cell Biol . 1998;  143 1485-1503
    CrossrefPubMedGoogle Scholar
  • 55 McNiven M A. Dynamin: A molecular motor with pinchase action.  Cell . 1998;  94 151-154
    CrossrefPubMedGoogle Scholar
  • 56 Keller P, Simons K. Post-Golgi biosynthetic trafficking.  J Cell Sci . 1997;  110 3001-3009
    PubMedGoogle Scholar
  • 57 Lippincott-Schwartz J. Cytoskeletal proteins and Golgi dynamics.  Curr Opin Cell Biol . 1998;  10 52-59
    CrossrefPubMedGoogle Scholar
  • 58 Traub L M, Kornfeld S. The trans-Golgi network: A late secretory sorting station.  Curr Opin Cell Biol . 1997;  9 527-533
    CrossrefPubMedGoogle Scholar
  • 59 Mellman I, Warren G. The road taken: Past and future foundations of membrane traffic.  Cell . 2000;  100 99-112
    CrossrefPubMedGoogle Scholar