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 journalArticle

20 Citations (Scopus)

Abstract

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
Volume13
Issue number8
StatePublished - 1999

Fingerprint

cyclic GMP
Enterotoxins
enterotoxins
Diarrhea
diarrhea
Cyclic GMP
guanylate cyclase
secretion
Chlorides
chlorides
Water
Intestinal Secretions
cells
Guanylate Cyclase
water
therapeutics
2-Chloroadenosine
chloride channels
Cystic Fibrosis Transmembrane Conductance Regulator
Chloride Channels

Keywords

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

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Zhang, W., Mannan, I., Schulz, S., Parkinson, S. J., Alekseev, A. E., Gomez, L. A., ... Waldman, S. A. (1999). Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea. FASEB Journal, 13(8), 913-922.

Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea. / Zhang, Wei; Mannan, Ishrat; Schulz, Stephanie; Parkinson, Scott J.; Alekseev, Alexey E.; Gomez, Luis A.; Terzic, Andre; Waldman, Scott A.

In: FASEB Journal, Vol. 13, No. 8, 1999, p. 913-922.

Research output: Contribution to journalArticle

Zhang, W, Mannan, I, Schulz, S, Parkinson, SJ, Alekseev, AE, Gomez, LA, Terzic, A & Waldman, SA 1999, 'Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea', FASEB Journal, vol. 13, no. 8, pp. 913-922.
Zhang W, Mannan I, Schulz S, Parkinson SJ, Alekseev AE, Gomez LA et al. Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea. FASEB Journal. 1999;13(8):913-922.
Zhang, Wei ; Mannan, Ishrat ; Schulz, Stephanie ; Parkinson, Scott J. ; Alekseev, Alexey E. ; Gomez, Luis A. ; Terzic, Andre ; Waldman, Scott A. / Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea. In: FASEB Journal. 1999 ; Vol. 13, No. 8. pp. 913-922.
@article{7a1961a971f74971b3e546e4a71e5459,
title = "Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea",
abstract = "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.",
keywords = "2-substituted adenine nucleotides, CFTR-mediated chloride current, Cyclic GMP, E. coli heat-stable enterotoxin, Intestinal cell water secretion",
author = "Wei Zhang and Ishrat Mannan and Stephanie Schulz and Parkinson, {Scott J.} and Alekseev, {Alexey E.} and Gomez, {Luis A.} and Andre Terzic and Waldman, {Scott A.}",
year = "1999",
language = "English (US)",
volume = "13",
pages = "913--922",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "8",

}

TY - JOUR

T1 - Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea

AU - Zhang, Wei

AU - Mannan, Ishrat

AU - Schulz, Stephanie

AU - Parkinson, Scott J.

AU - Alekseev, Alexey E.

AU - Gomez, Luis A.

AU - Terzic, Andre

AU - Waldman, Scott A.

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

KW - 2-substituted adenine nucleotides

KW - CFTR-mediated chloride current

KW - Cyclic GMP

KW - E. coli heat-stable enterotoxin

KW - Intestinal cell water secretion

UR - http://www.scopus.com/inward/record.url?scp=0032896023&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032896023&partnerID=8YFLogxK

M3 - Article

C2 - 10224234

AN - SCOPUS:0032896023

VL - 13

SP - 913

EP - 922

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 8

ER -