A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion

Abstract

Luminal acidification provides the strongest physiological stimulus for duodenal HCO3- secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated HCO3- secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal HCO3- secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated HCO3- secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal HCO3- secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal HCO3- secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.

Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract

“…Moreover, the binding of STa to intestinal mucosal membranes from both wt and GC-C null mice was effectively competed away in the presence of excess linaclotide, potentially supporting the hypothesis of an alternative, non-GC-C receptor binding site on these cells. Although these two binding sites could constitute interchangeable low and high affinity binding states of the GC-C receptor (Crane et al 1992), several recent studies have provided evidence for a second, low affinity non-GC-C receptor, including the characterization of such a receptor in the proximal duodenum of GC-C null mice (Rao et al 2004;Sellers et al 2008). Functionally, this receptor is involved in the regulation of HCO 3 − secretion, but the observed increase in transepithelial HCO 3 − secretion after ST peptide binding in GC-C null mice is significantly attenuated in both magnitude and duration when compared to wt animals, suggesting that GC-C is the principal receptor for guanylin peptide-mediated regulation of intestinal fluid homeostasis.…”

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

“…We have previously demonstrated a defect in phosphorylation of extracellular-regulated kinase 1 and 2 (ERK1/2) in mice lacking GC-C. 10 Work with colon cancer cell lines has linked inhibition of epidermal growth factor-induced phosphorylation of ERK1/2 with apoptosis. 40,41 In Apc Min/1 mice expressing a mutant epidermal growth factor receptor, polyp number was reduced 90% compared to mice with wild-type receptor.…”

“…Functional studies established that while colonic ion transport is similar to that observed in wild-type mice, 9 bicarbonate secretion in the duodenum of GC-C null mice is greatly attenuated in response to acid, a major physiologic stimulus of secretion. 10 In both human and mouse intestine, GC-C is expressed in villus and crypt enterocytes of the small intestine as well as the surface epithelium and crypts of the colon. 11,12 The endogenous ligands for GC-C are expressed in an overlapping gradient, with uroguanylin expression highest in the proximal intestine and guanylin levels highest in the distal intestine.…”

Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells

“…ERK1/2 is also implicated in the regulation of intestinal ion transport (18), and some evidence links ERK1/2 with GC-C signaling in ion secretion (19). Caco-2 cells were preincubated in Ussing chambers with the ERK1/2 specific inhibitor, PD098059, for 30 min before GC-C activation.…”