Interruption of Escherichia coli heat-stable enterotoxin-induced guanylyl cyclase signaling and associated chloride current in human intestinal cells by 2-chloroadenosine.

The Journal of Biological Chemistry
S J ParkinsonS A Waldman

Abstract

Diarrhea induced by Escherichia coli heat-stable enterotoxin (STa) is mediated by a receptor guanylyl cyclase cascade. The present study establishes that an intracellular nucleotide-dependent pathway disrupts toxin-induced cyclic GMP (cGMP) production and the associated chloride (Cl-) flux that underlie intestinal secretion. Incubation of Caco 2 human intestinal epithelial cells with the nucleoside analog 2-chloroadenosine (2ClAdo) resulted in a concentration- and time-dependent inhibition of toxin-induced cGMP production. Inhibition of cGMP production correlated with the metabolic conversion of 2ClAdo to 2-chloroadenosine triphosphate. The effect of 2ClAdo did not reflect activation of adenosine receptors, inhibition of adenosine deaminase, or modification of the binding or distribution of STa receptors. Guanylyl cyclase activity in membranes prepared from 2ClAdo-treated cells was inhibited, in contrast to membranes from cells not exposed to 2ClAdo, demonstrating that inhibition of guanylyl cyclase C (GCC) was mediated by a noncompetitive mechanism. Treatment of Caco 2 cells with 2ClAdo also prevented STa-induced Cl- current. Application of 8-bromo-cGMP, the cell-permeant analog of cGMP, to 2ClAdo-treated cells reconstituted t...Continue Reading

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Citations

Feb 6, 2004·Toxicon : Official Journal of the International Society on Toxinology·Karina N LaohachaiJoseph I Kourie
Apr 30, 1998·Journal of the American College of Cardiology·P A Brady, A Terzic
May 3, 2002·European Journal of Biochemistry·Inez Ruiz-StewartScott A Waldman
Feb 21, 2003·Proceedings of the National Academy of Sciences of the United States of America·G M PitariS A Waldman
Sep 6, 2013·Microbiology and Molecular Biology Reviews : MMBR·Vanessa Liévin-Le Moal, Alain L Servin
Feb 27, 2010·Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B·Martin BeaulieuTimothy J Holzer
May 4, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·W ZhangS A Waldman
Dec 5, 2009·Molecular and Cellular Biochemistry·Nirmalya BasuSandhya S Visweswariah

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