5-Hydroxytryptamine contributes significantly to a reflex pathway by which the duodenal mucosa protects itself from gastric acid injury.
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
Anders J
AJ
Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0063, USA.
Chappell
Alfred E
AE
Buret
Andre G
AG
Barrett
Kim E
KE
Dong
Hui
H
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects / Q000502:physiology*; D005744:Gastric Acid / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D012018:Reflex / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D001639:Bicarbonates; D004146:Dioxanes; D010880:Piperidines; D012702:Serotonin Antagonists; D019831:Sodium-Calcium Exchanger; C084858:SB 204070A; D012701:Serotonin; D013890:Thiourea; D002118:Calcium