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MUCOSAL BIOLOGY
1Division of Gastroenterology, Department of Medicine, University of California San Diego, San Diego, California 92103; and 2Division of Digestive Diseases, University of Cincinnati and Veterans Affairs Medical Center, Cincinnati, Ohio 45267-0595
Submitted 21 February 2003 ; accepted in final form 17 July 2003
Luminal acidification provides the strongest physiological stimulus for duodenal 
secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated 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 secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal 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 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 secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal secretion.
acid-stimulated bicarbonate secretion; extracellular signal-related kinase phosphorylation; intracellular signaling
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