Skip to main content
Log in

Guanylin and functional coupling proteins in the hepatobiliary system of rat and guinea pig

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Guanylin, a bioactive intestinal peptide, is involved in the cystic fibrosis transmembrane conductance (CFTR)-regulated electrolyte/water secretion in various epithelia. In the present work we report on the expression and cellular localization of guanylin and its affiliated signaling and effector proteins, including guanylate cyclase C (Gucy2c), Proteinkinase GII (Pkrg2), CFTR and the solute carrier family 4, anion exchanger, member 2 (Slc4a2) in the hepatobiliary system of rat and guinea pig. Localization studies in the liver and the gallbladder revealed that guanylin is located in the secretory epithelial cells of bile ducts of the liver and of the gallbladder, while Gucy2c, Pkrg2, CFTR, and Slc4a2 are confined exclusively to the apical membrane of the same epithelial cells. Based on these findings, we assume that guanylin is synthesized as an intrinsic peptide in epithelial cells of the hepatobiliary system and released luminally into the hepatic and cystic bile to regulate electrolyte secretion by a paracrine/luminocrine signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Buccigrossi V, Armellino C, Ruberto E, Barone MV, Marco GD, Esposito C, Guarino A (2011) Polar effects on ion transport and cell proliferation induced by gc-c ligands in intestinal epithelial cells. Pediatr Res 69(1):17–22

    Article  PubMed  CAS  Google Scholar 

  • Cetin Y, Bargsten G, Grube D (1992) Mutual relationships between chromogranins A and B and gastrin in individual gastrin cells. Proc NatI Acad Sci USA 89:2912–2916

    Article  CAS  Google Scholar 

  • Cetin Y, Aunis D, Bader MF, Galindo E, Jörns A, Bargsten G, Grube D (1993) Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells. Proc NatI Acad Sci USA 90:2360–2364

    Article  CAS  Google Scholar 

  • Cetin Y, Kuhn M, Kulaksiz H, Adermann K, Bargsten G, Grube D, Forssmann WG (1994) Enterchromaffin cells of the digestive system: celluluar source of guanylin, a guanylate cyclase-activating peptide. Proc NatI Acad Sci USA 91:2935–2939

    Article  CAS  Google Scholar 

  • Cetin Y, Kulaksiz H, Redecker P, Bargsten G, Adermann K, Grube D, Forssmann WG (1995) Bronchiolar nonciliated secretory (Clara) cells: source of guanylin in the mammalian lung. Proc NatI Acad Sci USA 92:5929–59925

    Article  Google Scholar 

  • Cuthbert AW, Hickman ME, MacVinish LJ, Evans MJ, Colledge WH, Ratcliff R, Seale PW, Humphrey PPA (1994) Chloride secretion in response to guanylin in colonic epithelia from normal and transgenic cysic fibrosis mice. Br J Pharmacol 122:31–36

    Google Scholar 

  • Dodgson SJ, Foster RE 2nd (1986) Carbonic anhydrase: inhibition results in decreased urea production by hepatocytes. J Appl Physiol 60:646–652

    PubMed  CAS  Google Scholar 

  • Fonteles MC, do Nascimento NR (2011) Guanylin peptide family: history, interactions with ANP, and new pharmacological perspectives. Can J Physiol Pharmacol 89(8):575–585

    Article  PubMed  CAS  Google Scholar 

  • Forte LR, Eber SL, Turner JT, Freeman RH, Fok KF, Currie MG (1993) Guanylin stimulation of Cl–secretion in human intestinal T84 cells via cyclic guanosine monophosphate. J Clin Invest 91:2423–2428

    Article  PubMed  CAS  Google Scholar 

  • Fuller CM, Benos DJ (1992) CFTR! Am J Physiol 263:C267–C286

    PubMed  CAS  Google Scholar 

  • Garbers DL (1992) Guanylyl cyclase receptors and their endocrine, paracrine, and autocrine ligands. Cell 71:1–4

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Marin JJ, Peez-Barriocanal F, Garcia A, Serrano MA, Requeiro P, Esteller A (1988) Evidence for the presence of carbonic anhydrase in the plasma membrane of the rat hepatocytes. Biochim Biophys Acta 945:2–17

    Google Scholar 

  • Guba M, Kuhn M, Forssmann WG, Classen M, Gregor M, Seidler U (1996) Guanylin strongly stimulates rat duodenal HCO3 secretion: proposed mechanism and comparison with other secretagogues. Gastroenterology 111:1558–1568

    Article  PubMed  CAS  Google Scholar 

  • Hamra FK, Forte LR, Eber SL, Pidhorodeckyj NV, Krause WJ, Freeman RH, Chin DT, Tompkins JA, Fok KF, Smith CE et al (1993) Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase. Proc NatI Acad Sci USA 90:10464–10468

    Article  CAS  Google Scholar 

  • Hamra FK, Krause WJ, Eber SL, Freeman RH, Smith CE, Currie MG, Forte LR (1996) Opossum colonic mucosa contains uroguanylin and guanylin peptides. Am J Physio 270:G708–G716

    CAS  Google Scholar 

  • Hamra FK, Eber SL, Chin DT, Currie MG, Forte LR (1997) Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity. Proc NatI Acad Sci USA 94:2705–2710

    Article  CAS  Google Scholar 

  • Joo NS, London RM, Kim HD, Forte LR, Clarke LL (1998) Regulation of intestinal Cl and HCO3 secretion by uroguanylin. Am J Physiol 274:G633–G644

    PubMed  CAS  Google Scholar 

  • Kulaksiz H, Cetin Y (2001) Uroguanylin and guanylate cyclase C in the human pancreas: expression and mutuality of ligand/receptor localization as indicators of intercellular paracrine signaling pathways. J Endocrinol 170:267–275

    Article  PubMed  CAS  Google Scholar 

  • Kulaksiz H, Rausch U, Vaccaro R, Renda TG, Cetin Y (2001a) Guanylin and uroguanylin in the parotid and submandibular glands: potential intrinsic regulators of electrolyte secretion in salivary glands. Histochem Cell Biol 115:527–533

    Article  PubMed  CAS  Google Scholar 

  • Kulaksiz H, Schmid A, Hönscheid M, Eissele R, Klempnauer J, Cetin Y (2001b) Guanylin in the human pancreas: a novel luminocrine regulatory pathway of electrolyte secretion via cGMP and CFTR in the ductal system. Histochem Cell Biol 115:131–145

    Article  PubMed  CAS  Google Scholar 

  • Kulaksiz H, Rehberg E, Stremmel W, Cetin Y (2002a) Guanylin and functional coupling proteins in the human salivary glands and gland tumors. Am J Pathol 161:655–664

    Article  PubMed  CAS  Google Scholar 

  • Kulaksiz H, Schmid A, Hönscheid M, Ramaswamy A, Cetin Y (2002b) Clara cell impact in air-side activation of CFTR in small pulmonary airways. Proc NatI Acad Sci USA 99:6796–6801

    Article  CAS  Google Scholar 

  • Kulaksiz H, Schlenker T, Rost D, Stiehl A, Volkmann M, Lehnert T, Cetin Y, Stremmel W (2004) Guanylin regulates chloride secretion in the human gallbladder via the bile fluid. Gastroenterology 126:732–740

    Article  PubMed  CAS  Google Scholar 

  • Lee MG, Choi JY, Luo X, Strickland E, Thomas PJ, Muallem S (1999a) Cystic fibrosis transmembrane conductance regulator regulates luminal Cl-/HCO3–exchange in mouse submandibular and pancreatic ducts. J Biol Chem 274:14670–14677

    Article  PubMed  CAS  Google Scholar 

  • Lee MG, WIgley WC, Zeng W, Noel LE, Marino CR, Thomas PJ, Muallem S (1999b) Regulation of Cl-/HCO3–exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells. J Biol Chem 274:3414–3421

    Article  PubMed  CAS  Google Scholar 

  • Lewis LG, Witte DP, Laney DW, Currie MG, Cohen MB (1993) Guanylin mRNA is expressed in villous enterocytes of the rat small intestine and superficial epithelia of the rat colon. Biochem Biophys Res Commun 196:553–560

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Taylor-Blake B, Light AR, Goy MF (1995) Guanylin, an endogenous ligand for C-type guanylate cyclase is produced by goblet cells in the rat intestine. Gastroenterology 109:1863–1875

    Article  PubMed  CAS  Google Scholar 

  • Lipsen B, Effros RM (1988) CO2 and bicarbonate exchange in the rat liver. J Appl Physiol 65:2736–2743

    PubMed  CAS  Google Scholar 

  • London RM, Krause WJ, Fan X, Eber SL, Forte LR (1997) Signal transduction pathways via guanylin and uroguanylin in stomach and intestine. Am J Physiol 273:G93–G105

    PubMed  CAS  Google Scholar 

  • Miyazato M, Nakazato M, Matsukura S, Kangawa K, Matsuo H (1996) Uroguanylin gene expression in the alimentary tract and extra-gastrointestinal tissues. FEBS Lett 398:170–174

    Article  PubMed  CAS  Google Scholar 

  • Parkkila S, Parkkila AK, Juvonen T, Waheed A, Sly WS, Saarnio J, Kaunisto K, Kellokumpu S, Rajaniemi H (1996) Membrane-bound carbonic anhydrase IV is expressed in the luminal plasma membrane of the human gallbladder epithelium. Hepatology 24:1104–1108

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fässler R (1996) Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II. Science 274:2082–2086

    Article  Google Scholar 

  • Quinton PM (1999) Physiological basis of cystic fibrosis: a historical perspective. Physiol Rev 79:S3–S22

    PubMed  CAS  Google Scholar 

  • St. Pierre MV, Schlenker T, Dufour JF, Jefferson DM, Fitz JG, Arias IM (1998) Stimulation of cyclic guanosine monophosphate production by natriuretic peptide in human biliary cells. Gastroenterology 114:782–790

    Article  PubMed  CAS  Google Scholar 

  • Sterling D, Reithmeier RA, Casey JR (2001) Carbonic anhydrase: in the driver’s seat for bicarbonate transport. JOP 2:165–170

    PubMed  CAS  Google Scholar 

  • Vaandrager AB (2002) Structure and function of the heat-stable enterotoxin receptor/guanylyl cyclase C. Mol Cell Biochem 230:73–83

    Article  PubMed  CAS  Google Scholar 

  • Vaandrager AB, Smolenski A, Tilly BC, Houtsmuller AB, Ehlert EME, Bot AGM, Edixhoven M, Boomaars WEM, Lohmann SM, de Jonge HR (1998) Membrane targeting of cGMP-dependent protein kinase is required for cystic fibrosis transmembrane conductance regulator Cl channel activation. Proc NatI Acad Sci USA 95:1466–1471

    Article  CAS  Google Scholar 

  • Vaccaro R, Cetin Y, Renda TG (2004) Ontogeny of guanylin-immunoreactive cells in rat salivary glands. Anat Embryol (Berl) 208:65–73

    Article  CAS  Google Scholar 

  • Wilhelm B, Keppler C, Hoffbauer G, Lottspeich F, Linder D, Meinhardt A, Aumüller G, Seitz J (1998) Cytoplasmic carbonic anhydrase II of rat coagulating gland is secreted via the apocrine export mode. J Histochem Cytochem 46:505–511

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank for the experimental help of M. Meier during her doctoral thesis in the department. The technical assistance of C. Merte-Grebe and T. Seitz is greatly acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yalcin Cetin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schwabe, K., Cetin, Y. Guanylin and functional coupling proteins in the hepatobiliary system of rat and guinea pig. Histochem Cell Biol 137, 589–597 (2012). https://doi.org/10.1007/s00418-012-0927-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-012-0927-2

Keywords

Navigation