title: Heat-stable enterotoxin of Escherichia coli stimulates a non-CFTR-mediated duodenal bicarbonate secretory pathway.
abstract: 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.
authors.affiliation: Div. of Gastroenterology (8414 University of California San Diego Medical Center, 200 West Arbor Dr., San Diego, CA 92103-8414, USA.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Sellers
authors.forename: Debbie
authors.initials: D
authors.lastname: Childs
authors.forename: Jimmy Y C
authors.initials: JY
authors.lastname: Chow
authors.forename: Anders J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hogan
authors.forename: Jon I
authors.initials: JI
authors.lastname: Isenberg
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.forename: Kim E
authors.initials: KE
authors.lastname: Barrett
authors.forename: Vijaya S
authors.initials: VS
authors.lastname: Pratha
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D016227:Benzoquinones; D001639:Bicarbonates / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism*; D004768:Enterotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D029968:Escherichia coli Proteins; D019833:Genistein / Q000494:pharmacology; D066298:In Vitro Techniques; D047029:Lactams, Macrocyclic; D051379:Mice; D045265:Natriuretic Peptides; D010455:Peptides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives
chemical_list: D001427:Bacterial Toxins; D016227:Benzoquinones; D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D004768:Enterotoxins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D047029:Lactams, Macrocyclic; D045265:Natriuretic Peptides; D010455:Peptides; D011809:Quinones; C034151:heat stable toxin (E coli); C084362:uroguanylin; D005576:Colforsin; D017828:Rifabutin; C016276:8-bromocyclic GMP; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D006152:Cyclic GMP