Abstract
Guanylin receptor guanylate cyclase (GC-C) peaks in neonatal intestine and is involved in either enterocyte proliferation or chloride secretion. The latter is more potent when GC-C activator guanylin, or its analog Escherichia coli heat-stable enterotoxin (ST), is added to the mucosal rather than serosal side of intestinal monolayers. By using Ussing chambers, we investigated transepithelial ion transport and enterocyte proliferation and their mechanisms in response to the addition of guanylin or ST to the mucosal or serosal side of Caco-2 monolayers and in ileal specimens from neonates. GC-C activation showed a polar pattern of the effects. GC-C mucosal activation resulted in a potent cGMP-chloride secretion activation and in a marginal enterocyte proliferation. Conversely, serosal GC-C activation induced a potent enterocyte proliferation, through MAP kinase ERK 1/2. Finally, the inhibition of ERK1/2 enhanced the Isc increase in response to serosal but not to mucosal ST stimulation, indicating that ERK1/2 also acts as a brake of chloride secretion. These data suggest that the guanylin/GC-C system plays a key role in early postnatal intestinal adaptation exploiting the polar structure of enterocyte.
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Abbreviations
- GC-C:
-
intestinal guanylate cyclase
- BrdU:
-
bromodeoxyuridine
- ERK:
-
extracellular signal-regulated kinase
- ST:
-
E. coli heat stable enterotoxin toxin
- Caco-2 cells:
-
human colonic adenocarcinoma cells
- M:
-
mucosal side
- S:
-
serosal side
References
Pinto D, Clevers H 2005 Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res 306: 357–363
Höfer D, Jöns T, Kraemer J, Drenckhahn D 1998 From cytoskeleton to polarity and chemoreception in the gut epithelium. Ann N Y Acad Sci 859: 75–84
Forte LR 1999 Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology. Regul Pept 81: 25–39
Giannella RA, Mann EA 2003 E. coli heat-stable enterotoxin and guanylyl cyclase C: new functions and unsuspected actions. Trans Am Clin Climatol Assoc 114: 67–85
Kuhn M 2009 Function and dysfunction of mammalian membrane guanylyl cyclase receptors: lessons from genetic mouse models and implications for human diseases. Handb Exp Pharmacol 191: 47–69
Krause WJ, Cullingford GL, Freeman RH, Eber SL, Richardson KC, Fok KF, Currie MG, Forte LR 1994 Distribution of heat-stable enterotoxin/guanylin receptors in the intestinal tract of man and other mammals. J Anat 184: 407–417
Cohen MB, Guarino A, Giannella RA 1988 Age-related differences in receptors for Escherichia coli heat-stable enterotoxin in the small and large intestine of children. Gastroenterology 94: 367–373
Albano F, Brasitus T, Mann EA, Guarino A, Giannella RA 2001 Colonocyte basolateral membranes contain Escherichia coli heat-stable enterotoxin receptors. Biochem Biophys Res Commun 284: 331–334
Albano F, De Marco G, Berni Canani R, Cirillo P, Buccigrossi V, Giannella RA, Guarino A 2005 Guanylin and E. coli heat-stable enterotoxin induce chloride secretion through direct interaction with basolateral compartment of rat and human colonic cells. Pediatr Res 58: 159–163
Guarino A, Cohen MB, Giannella RA 1987 Small and large intestinal guanylate cyclase activity in children: effect of age and stimulation by Escherichia coli heat-stable enterotoxin. Pediatr Res 21: 551–555
Bełtowski J 2001 Guanylin and related peptides. J Physiol Pharmacol 52: 351–375
Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM 2007 Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine. Am J Pathol 171: 1847–1858
Steinbrecher KA, Wowk SA, Rudolph JA, Witte DP, Cohen MB 2002 Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation. Am J Pathol 161: 2169–2178
Garin-Laflam MP, Steinbrecher KA, Rudolph JA, Mao J, Cohen MB 2009 Activation of guanylate cyclase C signaling pathway protects intestinal epithelial cells from acute radiation-induced apoptosis. Am J Physiol Gastrointest Liver Physiol 296: G740–G749
Aliaga JC, Deschenes C, Beaulieu JF, Calvo EL, Rivard N 1999 Requirement of the MAP kinase cascade for cell cycle progression and differentiation of human intestinal cells. Am J Physiol 277: G631–G641
Watson AJ, Levine S, Donowitz M, Montrose MH 1991 Kinetics and regulation of a polarized Na(+)-H+ exchanger from Caco-2 cells, a human intestinal cell line. Am J Physiol 261: G229–G238
Visco V, Belleudi F, Marchese C, Leone L, Aimati L, Cardinali G, Kovacs D, Frati L, Torrisi MR 2004 Differential response to keratinocyte growth factor receptor and epidermal growth factor receptor ligands of proliferating and differentiating intestinal epithelial cells. J Cell Physiol 200: 31–44
Chow JY, Carlstrom K, Barrett KE 2003 Growth hormone reduces chloride secretion in human colonic epithelial cells via EGF receptor and extracellular regulated kinase. Gastroenterology 125: 1114–1124
Rao SP, Sellers Z, Crombie DL, Hogan DL, Mann EA, Childs D, Keely S, Sheil-Puopolo M, Giannella RA, Barrett KE, Isenberg JI, Pratha VS 2004 A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol 286: G95–G101
Rudolph JA, Poccia JL, Cohen MB 2004 Cyclic AMP activation of the extracellular signal-regulated kinases 1 and 2: implications for intestinal cell survival through the transient inhibition of apoptosis. J Biol Chem 279: 14828–14834
Rhoads M 1999 Glutamine signaling in intestinal cells. JPEN J Parenter Enteral Nutr 23: S38–S40
Rowland KJ, Brubaker PL 2008 Life in the crypt: a role for glucagon-like peptide-2. Mol Cell Endocrinol 288: 63–70
Guillermet-Guibert J, Lahlou H, Cordelier P, Bousquet C, Pyronnet S, Susini C 2005 Physiology of somatostatin receptors. J Endocrinol Invest 28: 5–9
Buccigrossi V, De Marco G, Bruzzese E, Ombrato L, Bracale I, Polito G, Guarino A 2007 Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res 61: 410–414
Lin TY, Chiou SH, Chen M, Kuo CD 2005 Human lactoferrin exerts bi-directional actions on PC12 cell survival via ERK1/2 pathway. Biochem Biophys Res Commun 337: 330–336
Jin XH, Siragy HM, Guerrant RL, Carey RM 1999 Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum. J Clin Invest 103: 167–174
Massey-Harroche D 2000 Epithelial cell polarity as reflected in enterocytes. Microsc Res Tech 49: 353–362
Boucher MJ, Rivard N 2003 Regulation and role of brush border-associated ERK1/2 in intestinal epithelial cells. Biochem Biophys Res Commun 311: 121–128
Boucher MJ, Jean D, Vézina A, Rivard N 2004 Dual role of MEK/ERK signaling in senescence and transformation of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 286: G736–G746
Halbleib JM, Sääf AM, Brown PO, Nelson WJ 2007 Transcriptional modulation of genes encoding structural characteristics of differentiating enterocytes during development of a polarized epithelium in vitro. Mol Biol Cell 18: 4261–4278
Ghanekar Y, Chandrashaker A, Visweswariah SS 2003 Cellular refractoriness to the heat-stable enterotoxin peptide is associated with alterations in levels of the differentially glycosylated forms of guanylyl cyclase C. Eur J Biochem 270: 3848–3857
Qian X, Prabhakar S, Nandi A, Visweswariah SS, Goy MF 2000 Expression of GC-C, a receptor-guanylate cyclase, and its endogenous ligands uroguanylin and guanylin along the rostrocaudal axis of the intestine. Endocrinology 141: 3210–3224
Anand RJ, Leaphart CL, Mollen KP, Hackam DJ 2007 The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock 27: 124–133
Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA 2007 Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology 133: 599–607
Bryant AP, Busby RW, Bartolini WP, Cordero EA, Hannig G, Kessler MM, Pierce CM, Solinga RM, Tobin JV, Mahajan-Miklos S, Cohen MB, Kurtz CB, Currie MG 2010 Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 86: 760–765
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We thank Fabio Albano for very helpful comments on earlier versions of this article.
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Supported by a grant from the Italian Ministry of University and Scientific Research; Progetti di Ricerca di Interesse Nazionale—PRIN 2007.
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Buccigrossi, V., Armellino, C., Ruberto, E. et al. Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells. Pediatr Res 69, 17–22 (2011). https://doi.org/10.1203/PDR.0b013e3181ff61ba
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DOI: https://doi.org/10.1203/PDR.0b013e3181ff61ba
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