Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea

Wei Zhang, Ishrat Mannan, Stephanie Schulz, Scott J. Parkinson, Alexey E. Alekseev, Luis A. Gomez, Andre Terzic, Scott A. Waldman

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Bacteria that produce heat-stable enterotoxins (STs), a leading cause of secretory diarrhea, are a major cause of morbidity and mortality worldwide. ST stimulates guanylyl cyclase C (GCC) and accumulation of intracellular cyclic GMP ([cGMP](i)), which opens the cystic fibrosis transmembrane conductance regulator (CFTR)-related chloride channel, triggering intestinal secretion. Although the signaling cascade mediating ST-induced diarrhea is well characterized, antisecretory therapy targeting this pathway has not been developed. 2-ChloroATP (2C1ATP) and its cell-permeant precursor, 2- Chloroadenosine (2CIAdo), disrupt ST-dependent signaling in intestinal cells. However, whether the ability to disrupt guanylyl cyclase signaling translates into effective antisecretory therapy remains untested. In this study, the efficacy of 2CIAdo to prevent ST-induced water secretion by human intestinal cells was examined. In Caco-2 human intestinal cells, ST increased [cGMP](i), induced a chloride current, and stimulated net basolateral-tozapical water secretion. This effect on chloride current and water secretion was mimicked by the cell-permeant analog of cGMP, 8-bromo-cGMP. Treatment of Caco-2 cells with 2ClAdo prevented ST-induced increases in [cGMP](i), chloride current and water secretion. Inhibition of the downstream consequences of ST-GCC interaction reflects proximal disruption of cGMP production because 8-bromo- cGMP stimulated chloride current and water secretion in 2ClAdo-treated cells. Thus, this study demonstrates that disruption of guanylyl cyclase signaling is an effective strategy for antisecretory therapy and provides the basis for developing mechanism-based treatments for enterotoxigenic diarrhea.

Original languageEnglish (US)
Pages (from-to)913-922
Number of pages10
JournalFASEB Journal
Issue number8
StatePublished - 1999


  • 2-substituted adenine nucleotides
  • CFTR-mediated chloride current
  • Cyclic GMP
  • E. coli heat-stable enterotoxin
  • Intestinal cell water secretion

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


Dive into the research topics of 'Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea'. Together they form a unique fingerprint.

Cite this