Semin Liver Dis 2002; 22(3): 241-250
DOI: 10.1055/s-2002-34502
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Regulation of Cholangiocyte Secretion

J. Gregory Fitz
  • Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
Further Information

Publication History

Publication Date:
02 October 2002 (online)

ABSTRACT

Observations from a variety of model systems suggest that ductular bile formation is mediated in large part by transepithelial transport of Cl- ions and have identified Cl- channels in the apical membrane as important targets for hormones and other factors that modulate bile volume and composition through effects on duct cells. Signaling through secretin receptors that stimulate adenylyl cyclase and activate the cystic fibrosis transmembrane regulator (CFTR) Cl- channels represents a prototype for cholangiocyte secretion. However, recent observations indicate that cholangiocytes also express a variety of receptors that modulate secretory responses in the absence of effects on cyclic adenosine monophosphate (cAMP), and Cl- channels unrelated to CFTR have been identified. Moreover, rapid exocytosis of subapical vesicles is coupled closely to different Cl- secretory responses. These observations suggest that the protein composition of the apical domain is regulated by selective exocytosis and endocytosis of channel-containing vesicles, leading to rapid modulation of the transport capacity of individual cells in response to changing physiologic demands.

REFERENCES

  • 1 Wheeler H O, Ramos O L. Determinants of the flow and composition of bile in the unanesthetized dog during constant infusions of sodium taurocholate.  J Clin Invest . 1960;  39 161-170
  • 2 Farouk M, Vigna S R, McVey D C, Meyers W C. Localization and characterization of secretin binding sites expressed by rat bile duct epithelium.  Gastroenterology . 1992;  102 963-968
  • 3 Levine R A, Hall R C. Cyclic AMP in secretin choleresis. Evidence for a regulatory role in man and baboons but not in dogs.  Gastroenterology . 1976;  70 537-544
  • 4 Lenzen R, Elster J, Behrend C, Hampel K-E, Bechstein W-O, Neuhaus P. Bile acid-independent bile flow is differentially regulated by glucagon and secretin in humans after orthotopic liver transplantation.  Hepatology . 1997;  26 1272-1281
  • 5 Ballatori N, Truong A T. Relation between biliary glutathione excretion and bile acid-independent bile flow.  Am J Physiol . 1989;  256 G22-G30
  • 6 Fitz J G. Cellular mechanisms of bile secretion. In: Zakim D, Boyer TD, eds. Hepatology Philadelphia, PA: W.B. Saunders 1996: 362-376
  • 7 Doctor R B, Dahl R H, Salter K D, Fitz J G. Reorganization of cholangiocyte membrane domains represents an early event in rat liver ischemia.  Hepatology . 1999;  29 1364-1374
  • 8 Doctor R B, Dahl R H, Salter K D, Fouassier L, Chen J, Fitz J G. ATP depletion in rat cholangiocytes leads to marked internalization of membrane proteins.  Hepatology . 2000;  31 1045-1054
  • 9 Clarke L L, Grubb B R, Yankaskas J, Cotton C U, McKenzie A, Boucher R C. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in cftr(-/-) mice.  Proc Natl Acad Sci U S A . 1994;  91 479-483
  • 10 Huflejt M E, Blum R A, Miller S G, Moore H-PH, Machen T E. Regulated Cl transport, K and Cl permeability and exocytosis in T84 cells.  J Clin Invest . 1994;  93 1900-1910
  • 11 Roberts S K, Kuntz S M, Gores G, LaRusso N. Regulation of bicarbonate-dependent ductular bile secretion assessed by lumenal micropuncture of isolated rodent intrahepatic bile ducts.  Proc Natl Acad Sci U S A . 1993;  90 9080-9084
  • 12 Mennone A, Alvaro D, Cho W, Boyer J L. Isolation of small polarized bile duct units.  Proc Natl Acad Sci U S A . 1995;  92 6527-6531
  • 13 Cohn J A, Strong T A, Picciotto M A. Localization of CFTR in human bile duct epithelial cells.  Gastroenterology . 1993;  105 1857-1864
  • 14 McGill J, Gettys T W, Basavappa S, Fitz J G. Secretin activates Cl channels in bile duct epithelial cells through a cAMP-dependent mechanism.  Am J Physiol . 1994;  266 G731-G736
  • 15 Alvaro D, Cho W K, Mennone A, Boyer J L. Effect of secretin on intracellular pH regulation in isolated rat bile duct epithelial cells.  J Clin Invest . 1993;  92 1314-1325
  • 16 Martinez-Anso E, Castillo J E, Diez J, Medina J F, Prieto J. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver.  Hepatology . 1994;  19 1400-1406
  • 17 Singh S K, Mennone A, Gigliozzi A, Fraioli F, Boyer J L. Cl--dependent secretory mechanisms in isolated rat bile duct epithelial units.  Am J Physiol . 2001;  281 G438-G446
  • 18 Marinelli R A, Tietz P S, Pham L D, Rueckert L, Agre P, LaRusso N F. Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes.  Am J Physiol . 1999;  276 G280-G286
  • 19 Roman R M, Feranchak A P, Salter K D, Wang Y, Fitz J G. Endogenous ATP regulates Cl- secretion in cultured human and rat biliary epithelial cells.  Am J Physiol . 1999;  276 G1391-G400
  • 20 Salter K D, Fitz J G, Roman R M. Domain-specific purinergic signaling in polarized rat cholangiocytes.  Am J Physiol Gastrointest Liver Physiol . 2000;  278 G492-G500
  • 21 Riordan J R, Rommens J M, Kerem B-S. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA.  Science . 1989;  245 1066-1073
  • 22 Prince L S, Peter K, Hatton S R. Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator requires a tyrosine-based signal.  J Biol Chem . 1999;  274 3602-3609
  • 23 Doctor R B, Dahl R H, Fouassier L, Kilic G, Fitz J G. Cholangiocytes exhibit dynamic, actin-dependent changes in membrane turnover.  Am J Physiol . 2002;  282 C1042-C1052
  • 24 Kilic G, Doctor R B, Fitz J G. Insulin stimulates membrane conductance in a liver cell line: Evidence for insertion of ion channels through a phosphoinositide 3-kinase-dependent mechanism.  J Biol Chem . 2001;  276 26762-26768
  • 25 Kato A, Gores G, LaRusso N. Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cAMP-mediated mechanism.  J Biol Chem . 1992;  267 15523-15529
  • 26 Marinelli R A, Pham L, Agre P, LaRusso N. Secretin promotes osmotic water transport in rat cholangiocytes by increasing aquaporin-1 water channels in plasma membrane. Evidence for secretin-induced vesicular translocation of aquaporin-1.  J Biol Chem . 1997;  272 12984-12988
  • 27 Tietz P S, Holma R T, Miller L J, LaRusso N. Isolation and characterization of rat cholangiocyte vesicles enriched in apical or basolateral membrane domains.  Biochemistry . 1995;  34 15436-15443
  • 28 Prince L S, Workman Jr B R, Marchase R B. Rapid endocytosis of the cystic fibrosis transmembrane conductance regulator chloride channel.  Proc Natl Acad Sci U S A . 1994;  91 5192-5196
  • 29 Loffing J, Moyer B D, McCoy D, Stanton B A. Exocytosis is not involved in activation of Cl- secretion via CFTR in Calu-3 airway epithelial cells.  Am J Physiol . 1998;  275 C913-C920
  • 30 Cho W K, Mennone A, Rydberg S A, Boyer J L. Bombesin stimulates bicarbonate secretion from rat cholangiocytes: implications for neural regulation of bile secretion.  Gastroenterology . 1997;  113 311-321
  • 31 Cho W K, Boyer J L. Vasoactive intestinal popypeptide is a potent regulator of bile secretion from rat cholangiocytes.  Gastroenterology . 1999;  117 420-428
  • 32 Alvaro D, Alpini G, Jezequel A M. Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions.  J Clin Invest . 1997;  100 1349-1362
  • 33 LeSage G, Alvaro D, Benedetti A. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats.  Gastroenterology . 1999;  117 191-199
  • 34 Roman R M, Feranchak A P, Salter K D, Wang Y, Fitz J G. Endogenous ATP release regulates Cl- secretion in cultured human and rat biliary epithelial cells.  Am J Physiol . 1999;  276 G1391-G1400
  • 35 Roman R M, Fitz J G. Emerging roles of purinergic signaling in gastrointestinal epithelial secretion and hepatobiliary function.  Gastroenterology . 1999;  116 964-979
  • 36 Roman R M, Wang Y, Fitz J G. Regulation of cell volume in a human biliary cell line: Calcium-dependent activation of K+ and Cl- currents.  Am J Physiol . 1996;  271 G239-G248
  • 37 Roman R M, Bodily K, Wang Y, Raymond J R, Fitz J G. Activation of protein kinase Ca couples cell volume to membrane Cl- permeability in HTC hepatoma and Mz-ChA-1 cholangiocarcinoma cells.  Hepatology . 1998;  28 1073-1080
  • 38 Feranchak A P, Roman R M, Doctor R B, Salter K D, Toker A, Fitz J G. The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport.  J Biol Chem . 1999;  274 30979-30986
  • 39 Merlin D, Guo X, Martin K. Recruitment of purinergically stimulated Cl- channels from granule membrane to plasma membrane.  Am J Physiol . 1996;  271 C612-C619
  • 40 McGill J, Gettys T W, Basavappa S, Fitz J G. GTP-binding proteins regulate high conductance anion channels in rat bile duct epithelial cells.  J Membr Biol . 1993;  133 253-261
  • 41 Schlenker T, Fitz J G. Calcium-activated chloride channels in a human biliary cell line: Regulation by calcium/calmodulin-dependent protein kinase.  Am J Physiol . 1996;  271 G304-G310
  • 42 Carew M A, Thorn P. Identification of ClC-2-like chloride currents in pig pancreatic acinar cells.  Pfluegers Arch . 1996;  433 84-90
  • 43 Xiong H, Garami E, Wang Y, Ramjeesingh M, Galley K, Bear C E. ClC-2 activation modulates regulatory volume decrease.  J Membr Biol . 1999;  167 215-221
  • 44 Roman R M, Smith R L, Feranchak A P, Clayton G H, Doctor R B, Fitz J G. ClC-2 chloride channels contribute to HTC cell volume homeostasis.  Am J Physiol . 2001;  280 G344-G353
  • 45 Strange K, Emma F, Jackson P S. Cellular and molecular physiology of volume-sensitive ion channels.  Am J Physiol . 1996;  270 C711-C730
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