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MUCOSAL BIOLOGY

Heat-stable enterotoxin of Escherichia coli stimulates a non-CFTR-mediated duodenal bicarbonate secretory pathway

Zachary M. Sellers, Debbie Childs, Jimmy Y. C. Chow, Anders J. Smith, Daniel L. Hogan, Jon I. Isenberg, Hui Dong, Kim E. Barrett, and Vijaya S. Pratha

Division of Gastroenterology, Department of Medicine, University of California, San Diego, California

Submitted 25 August 2004 ; accepted in final form 26 October 2004

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is an important pathway for duodenal mucosal bicarbonate secretion. Duodenal biopsies from CF patients secrete bicarbonate in response to heat-stable enterotoxin from Escherichia coli (STa) but not cAMP. To explore the mechanism of STa-induced bicarbonate secretion in CF more fully, we examined the role of CFTR in STa-stimulated duodenal bicarbonate secretion in mice. In vivo, the duodenum of CFTR (–/–) or control mice was perfused with forskolin (10^–4 M), STa (10^–7 M), uroguanylin (10^–7 M), 8-bromoguanosine 3',5'-cGMP (8-Br-cGMP) (10^–3 M), genistein (10^–6 M) plus STa, or herbimycin A (10^–6 M) plus STa. In vitro, duodenal mucosae were voltage-clamped in Ussing chambers, and bicarbonate secretion was measured by pH-stat. The effect of genistein, DIDS (10^–4 M), and chloride removal was also studied in vitro. Control, but not CF, mice produced a significant increase in duodenal bicarbonate secretion after perfusion with forskolin, uroguanylin, or 8-Br-cGMP. However, both control and CF animals responded to STa with significant increases in bicarbonate output. Genistein and herbimycin A abolished this response in CF mice but not in controls. In vitro, STa-stimulated bicarbonate secretion in CF tissues was inhibited by genistein, DIDS, and chloride-free conditions, whereas bicarbonate secretion persisted in control mice. In the CF duodenum, STa can stimulate bicarbonate secretion via tyrosine kinase activity resulting in apical Cl^–/HCO₃^– exchange. Further studies elucidating the intracellular mechanisms responsible for such non-CFTR mediated bicarbonate secretion may lead to important therapies for CF.

tyrosine kinase; cystic fibrosis; chloride/bicarbonate exchange

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