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J. Biol. Chem., Vol. 282, Issue 9, 6068-6074, March 2, 2007

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F508 Mutation Results in Impaired Gastric Acid Secretion^*

Shafik M. Sidani, Philipp Kirchhoff, Thenral Socrates, Lars Stelter, Elisa Ferreira^¶, Christina Caputo^¶, Kurt E. Roberts, Robert L. Bell, Marie E. Egan^¶||, and John P. Geibel^||1

From the Department of Surgery, Yale University, New Haven, Connecticut 06520, the ^||Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520, the ^¶Department of Pediatrics, Yale University, New Haven, Connecticut 06520, and the Department of Visceral and Transplantation Surgery, University of Zuerich, 8091 Zuerich, Switzerland

The cystic fibrosis transmembrane conductance regulator (CFTR) is recognized as a multifunctional protein that is involved in Cl^– secretion, as well as acting as a regulatory protein. In order for acid secretion to take place a complex interaction of transport proteins and channels must occur at the apical pole of the parietal cell. Included in this process is at least one K⁺ and Cl^– channel, allowing for both recycling of K⁺ for the H,K-ATPase, and Cl^– secretion, necessary for the generation of concentrated HCl in the gastric gland lumen. We have previously shown that an ATP-sensitive potassium channel (K_ATP) is expressed in parietal cells. In the present study we measured secretagogue-induced acid secretion from wild-type and F508-deficient mice in isolated gastric glands and whole stomach preparations. Secretagogue-induced acid secretion in wild-type mouse gastric glands could be significantly reduced with either glibenclamide or the specific inhibitor CFTR-inh172. In F508-deficient mice, however, histamine-induced acid secretion was significantly less than in wild-type mice. Furthermore, immunofluorescent localization of sulfonylurea 1 and 2 failed to show expression of a sulfonylurea receptor in the parietal cell, thus further implicating CFTR as the ATP-binding cassette transporter associated with the K_ATP channels. These results demonstrate a regulatory role for the CFTR protein in normal gastric acid secretion.

Received for publication, September 1, 2006 , and in revised form, December 13, 2006.

^* This work was supported by NIDDK, National Institutes of Health Grants DK007259-26 (to S. S.), DK07017-29 (to T. S.), DK53428 (to M. E.), and DK50230 and DK17433 (to J. G.) and by the Swiss National Foundation (Grant PBZHB-110427 to P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Surgery, Dept. of Cellular and Molecular Physiology, Yale University, BML 265, 310 Cedar St., New Haven, CT 06520. Tel.: 203-737-4152; Fax: 203-737-1464; E-mail: john.geibel{at}yale.edu.

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