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5-Hydroxytryptamine contributes significantly to a reflex pathway by which the duodenal mucosa protects itself from gastric acid injury

Anders J. Smith^*, Alfred E. Chappell^*, Andre G. Buret, Kim E. Barrett^* and Hui Dong^*,1

^* Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA; and

Department of Biology, University of Calgary, Alberta, Canada

¹Correspondence: Division of Gastroenterology, Department of Medicine, University of California, San Diego, 9500 Gilman Dr. La Jolla, CA 92093-0063, USA. E-mail: h2dong{at}ucsd.edu

Although duodenal mucosal bicarbonate secretion (DMBS) is currently accepted as an important defense mechanism against acid-induced duodenal injury, the mechanism and the regulation of DMBS are largely unknown. 5-HT may regulate DMBS, but little is known about its physiological relevance in DMBS and the underlying mechanism(s). Thus, the aims of the present study were to demonstrate the role of 5-HT in acid-stimulated DMBS and to further elucidate the precise mechanisms involved in this process. Luminal acid stimulation significantly increased 5-HT release from the duodenal mucosa (P<0.01). SB204070, a selective 5-HT₄ receptor antagonist, dose-dependently reduced luminal acid-stimulated HCO₃^– secretion of mice in vivo. In Ussing chamber studies, 5-HT-induced I_sc and DMBS were abolished by removal of extracellular Ca²⁺, and significantly attenuated by pharmacological blockade of the Na⁺/Ca²⁺ exchanger (NCX), intermediate Ca²⁺-activated K⁺ channels (IK_Ca), or cystic fibrosis transmembrane conductance regulator (CFTR). 5-HT increased cytoplasmic free calcium ([Ca²⁺]_cyt) in SCBN cells, a duodenal epithelial cell line, and knockdown of NCX1 proteins with a specific siRNA greatly decreased this 5-HT-mediated Ca²⁺ signaling. Taken together, our data suggest that 5-HT plays a physiological role in acid-stimulated DMBS via a Ca²⁺ signaling pathway, in which the plasma membrane NCX transporter as well as IK_Ca and CFTR channels may be involved.—Smith, A. J., Chappell, A. E., Buret, A. G., Barrett, K. E., Dong, H. 5-Hydroxytryptamine (5-HT) contributes significantly to a reflex pathway by which the duodenal mucosa protects itself from gastric acid injury.

Key Words: acid-stimulated 5-HT release • duodenal mucosal bicarbonate secretion • cytoplasmic Ca²⁺ signaling • Na⁺/Ca²⁺ exchanger

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