Studies on cholera-toxin-induced desensitization of adenylate cyclase in the mouse intestinal mucosa

Repeated peroral pretreatment ('immunization') with cholera toxin (CT) in mice induces protection against CT as well as against prostaglandin E1 (PGE1), as evaluated by fluid accumulation in intestinal loops. The fluid response to CT is depressed for more than 1 month, while the response to PGE1 is inhibited for 4-7 days after the pretreatment. Immunofluorescence microscopy revealed that neither the binding nor the penetration of CT into the intestinal epithelial cells is affected by the toxin pretreatment. Furthermore, the CT-induced release of mucus in goblet cells is not influenced by the toxin pretreatment. In contrast, the enzyme adenylate cyclase (AC), which mediates the actions of CT and PGE1, shows a long-lasting desensitization to CT, as estimated in mucosal membrane preparations. Chlorpromazine and cycloheximide revert the desensitization to CT as well as to PGE1. The present data suggest that intestinal resistance to CT in the mouse is due to desensitization of the reaction between CT and AC and requires stimulation of AC, as well as an active protein synthesis.