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1 Department of Pathology, Children's Hospital and Harvard Medical School, 2 Combined Program in Pediatric Gastroenterology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, and 3 Division of Gastroenterology, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115; 4 Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 5 Harvard Digestive Diseases Center, Boston, Massachusetts 02115
In intestinal epithelia, cholera and related toxins elicit a cAMP-dependent chloride secretory response fundamental to the pathogenesis of toxigenic diarrhea. We recently proposed that specificity of cholera toxin (CT) action in model intestinal epithelia may depend on the toxin's cell surface receptor ganglioside GM1. Binding GM1 enabled the toxin to elicit a response, but forcing the toxin to enter the cell by binding the closely related ganglioside GD1a rendered the toxin inactive. The specificity of ganglioside function correlated with the ability of GM1 to partition CT into detergent-insoluble glycosphingolipid-rich membranes (DIGs). To test the biological plausibility of these hypotheses, we examined native human intestinal epithelia. We show that human small intestinal epithelia contain DIGs that distinguish between toxin bound to GM1 and GD1a, thus providing a possible mechanism for enterotoxicity associated with CT. We find direct evidence for the presence of caveolin-1 in DIGs from human intestinal epithelia but find that these membranes are heterogeneous and that caveolin-1 is not a structural component of apical membrane DIGs that contain CT.
caveolae; cholera toxin; toxigenic diarrhea
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