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Am J Physiol Gastrointest Liver Physiol 277: G431-G444, 1999;
0193-1857/99 $5.00
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Vol. 277, Issue 2, G431-G444, August 1999

NSP4 elicits age-dependent diarrhea and Ca2+mediated Iminus influx into intestinal crypts of CF mice

Andrew P. Morris1, Jason K. Scott1, Judith M. Ball2, Carl Q.-Y. Zeng2, Wanda K. O'Neal3, and Mary K. Estes2

1 Departments of Integrative Biology and Internal Medicine-Gastroenterology, University of Texas at Houston Health Science Center, and 2 Divisions of Molecular Virology and Medicine-Gastroenterology and 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

Homologous disruption of the murine gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to the loss of cAMP-mediated ion transport. Mice carrying this gene defect exhibit meconium ileus at birth and gastrointestinal plugging during the neonatal period, both contributing to high rates of mortality. We investigated whether infectious mammalian rotavirus, the recently characterized rotaviral enterotoxin protein NSP4, or its active NSP4114-135 peptide, can overcome these gastrointestinal complications in CF (CFTRm3Bay null mutation) mice. All three agents elicited diarrhea when administered to wild-type (CFTR+/+), heterozygous (CFTR+/-), or homozygous (CFTR-/-) 7- to 14-day-old mouse pups but were ineffective when given to older mice. The diarrheal response was accompanied by non-age-dependent intracellular Ca2+ mobilization within both small and large intestinal crypt epithelia. Significantly, NSP4 elicited cellular I- influx into intestinal epithelial cells from all three genotypes, whereas both carbachol and the cAMP-mobilizing agonist forskolin failed to evoke influx in the CFTR-/- background. This unique plasma membrane halide permeability pathway was age dependent, being observed only in mouse pup crypts, and was abolished by either the removal of bath Ca2+ or the transport inhibitor DIDS. These findings indicate that NSP4 or its active peptide may induce diarrhea in neonatal mice through the activation of an age- and Ca2+-dependent plasma membrane anion permeability distinct from CFTR. Furthermore, these results highlight the potential for developing synthetic analogs of NSP4114-135 to counteract chronic constipation/obstructive bowel syndrome in CF patients.

cystic fibrosis transmembrane conductance regulator; halide permeability; NSP4 enterotoxin; rotavirus


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