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1 Cellular and Molecular Biology Program, The University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, MI, USA
2 Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, MI, USA
3 Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, USA
4 Unit for Laboratory Animal Medicine, The University of Michigan, Ann Arbor, MI, USA
5 Cellular and Molecular Biology Program, The University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, USA
6 Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: lcsam{at}umich.edu.
The stimulation of gastric acid secretion from parietal cells involves both intracellular calcium and cAMP signaling. To understand the affect of increased cAMP on parietal cell function we engineered transgenic mice expressing cholera toxin, an irreversible stimulator of adenylate cyclase. The parietal cell-specific H+, K+-ATPase 
-subunit promoter was used to drive expression of the cholera toxin A1 subunit (Ctox). Transgenic lines were established and tested for Ctox expression, acid content, plasma gastrin, tissue morphology and cellular composition of the gastric mucosa. Four lines were generated, with Ctox 7 expressing ~50-fold higher Ctox than the other lines. Enhanced cAMP signaling in parietal cells was confirmed by observation of hyperphosphorylation of the protein kinase A-regulated proteins LASP-1 and CREB. Basal acid content was elevated and circulating gastrin was reduced in Ctox transgenic lines. Analysis of gastric morphology revealed a progressive cellular transformation in Ctox 7. Expanded patches of mucous neck cells were observed as early as 3 months of age, and by 15 months extensive mucous cell metaplasia was observed in parallel with almost complete loss of parietal and chief cells. Detection of anti-parietal cell antibodies, inflammatory cell infiltrates, and increased expression of the Th1 cytokine interferon-
in Ctox 7 mice suggested that autoimmune destruction of the tissue caused atrophic gastritis. Thus, constitutively high parietal cell cAMP results in high acid secretion and a compensatory reduction in circulating gastrin. High Ctox in parietal cells can also induce progressive changes in the cellular architecture of the gastric glands corresponding to the development of anti-parietal cell antibodies and autoimmune gastritis.
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