IngentaConnect Genetic dissection of the signaling pathways that control gastric...

Authors: Chen, Duan¹; Friis-Hansen, Lennart²; Håkanson, Rolf³; Zhao, Chun-Mei⁴

Source: Inflammopharmacology, Volume 13, Numbers 1-3, 2005 , pp. 201-207(7)

Abstract:

Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three pathways, the gastrin–histamine pathway, the CCK–somatostatin pathway and the neural pathway. Genetically-engineered mice, subjected to targeted gene disruption (i.e., knockout mice), have been used to dissect the signaling pathways that are responsible for the complexity of the regulation of acid secretion in vivo. Both gastrin knockout and gastrin/CCK₂ receptor knockout mice displayed greatly impaired acid secretion, presumably because of the loss of the gastrin–histamine pathway. Gastrin/CCK double-knockout mice had a relatively high percentage of active parietal cells with a maintained ability to respond with copious acid secretion to pylorus ligation-evoked vagal stimulation and to a histamine challenge. The low acid secretion in gastrin knockout mice and gastrin/CCK₂ receptor knockout mice and the restoration of acid secretion in gastrin/CCK doubleknockout mice suggest that CCK plays an important role as inhibitor of the parietal cells via the CCK–somatostatin pathway by stimulating the CCK₁ receptor of the D cell. In the absence of both the gastrin–histamine and the CCK–somatostatin pathway (as in gastrin/CCK₂ receptor double-knockout mice), the control of acid secretion is probably taken over by neural pathways, explaining the high acid output. The observations illustrate the complexity and plasticity of the acid regulatory mechanisms. It seems that one pathway may be suppressed or allowed to dominate over the others depending on the circumstances.

Keywords: ACID SECRETION; CCK; GASTRIN; KNOCKOUT MICE; STOMACH

Document Type: Research article

DOI: 10.1163/156856005774423872

Affiliations: 1: Department of Surgery, University Hospital Trondheim, Olav Kyrres gate 17, 7006 Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway 2: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark 3: Department of Pharmacology, University of Lund, Lund, Sweden 4: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

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Genetic dissection of the signaling pathways that control gastric acid secretion