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1 Department of Medicine, Division of Gastroenterology, University of California, San Diego, San Diego, CA, USA
2 Division of Digestive Diseases, University of Cincinnati and VA Medical Center, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: vpratha{at}ucsd.edu.
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 E. coli heat-stable toxin (STa), both ligands of the transmembrane guanylyl cyclase receptor (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 in comparison to the WT counterparts. Pretreatment with PD98059, a 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 upon 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, while a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. Based on these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Further, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.
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