A role for CagA/VacA in Helicobacter pylori inhibition of murine duodenal mucosal bicarbonate secretion.
Duodenal mucosal bicarbonate secretion is diminished in patients with Helicobacter pylori (HP)-associated duodenal ulcer disease. We examined whether HP water extracts inhibit murine duodenal mucosal bicarbonate secretion in vitro, and the mechanisms involved. Murine duodenal mucosae were mounted in Ussing chambers. Short-circuit current and bicarbonate secretion was measured. CagA/VacA-positive HP water extract (HPWE+/+) markedly inhibited PGE2-, carbachol-, or the calcium ionophore A23187-stimulated bicarbonate secretion in a dose-dependent manner. While 3-isobutyl-1-methylxanthine-stimulated bicarbonate secretion was not affected by HPWE+/+, HPWE+/+ did diminish forskolin-stimulated bicarbonate secretion. HPWE+/+ markedly diminished PGE2-induced increases in duodenal mucosal cAMP. CagA/VacA of HP decreases Ca2+-mediated bicarbonate secretion downstream of increases in intracellular Ca2+. Dimunition of PGE2-stimulated bicarbonate secretion occurs, in part, by inhibition of adenylate cyclase, which leads to decreased cAMP levels. The ability of virulent HP strains to inhibit duodenal bicarbonate secretion through multiple intracellular pathways likely contributes to the pathogenesis of HP-associated duodenal ulcer disease.
Tuo
Bi-Guang
BG
Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, San Diego, California 92103, USA.
Sellers
Zachary M
ZM
Smith
Anders J
AJ
Barrett
Kim E
KE
Isenberg
Jon I
JI
Dong
Hui
H
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D004386:Duodenum / Q000378:metabolism; D016480:Helicobacter pylori / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001639:Bicarbonates; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D006152:Cyclic GMP; D002118:Calcium