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

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 288; no. 4; pp. G654 - G663
• Main Authors: Sellers, Zachary M, Childs, Debbie, Chow, Jimmy Y C, Smith, Anders J, Hogan, Daniel L, Isenberg, Jon I, Dong, Hui, Barrett, Kim E, Pratha, Vijaya S
• Format: Journal Article
• Language: English
• Published: United States 01.04.2005
• Subjects: Animals; Bacterial Toxins - pharmacology; Benzoquinones; Bicarbonates - metabolism; Cell Membrane - metabolism; Chloride-Bicarbonate Antiporters - metabolism; Colforsin - pharmacology; Cyclic GMP - analogs & derivatives; Cyclic GMP - pharmacology; Cystic Fibrosis - metabolism; Duodenum - metabolism; Enterotoxins - pharmacology; Enzyme Inhibitors - pharmacology; Escherichia coli Proteins; Genistein - pharmacology; In Vitro Techniques; Lactams, Macrocyclic; Mice; Natriuretic Peptides; Peptides - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Quinones - pharmacology; Rifabutin - analogs & derivatives
• DOI: 10.1152/ajpgi.00386.2004
• ISSN: 0193-1857

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(-)/HCO(3)(-) exchange. Further studies elucidating the intracellular mechanisms responsible for such non-CFTR mediated bicarbonate secretion may lead to important therapies for CF.