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

S. P. Rao, Z. Sellers, D. L. Crombie, D. L. Hogan, E. A. Mann, D. Childs, S. Keely, M. Sheil-Puopolo, R. A. Giannella, K. E. Barrett, J. I. Isenberg, Vijalakshmi S. Pratha

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15 Scopus citations

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 HCO 3- 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.

Original languageEnglish (US)
Pages (from-to)G95-G101
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume286
Issue number1 49-1
DOIs
StatePublished - Jan 2004

Keywords

  • Acid-stimulated bicarbonate secretion
  • Extracellular signal-related kinase phosphorylation
  • Intracellular signaling

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