Mechanism of activation of adenylate cyclase by Vibrio cholerae enterotoxin. Relations to the mode of activation by hormones.
The influence of Vibrio cholerae enterotoxin (choleragen) on the response of adenylate cyclase to hormones and GTP, and on the binding of 125I-labeled glucagon to membranes, has been examined primarily in rat adipocytes, but also in guinea pig ileal mucosa and rat liver. Incubation of fat cells with choleragen converts adenylate cyclase to a GTP-responsive state; (-)-isoproterenol has a similar effect when added directly to membranes. Choleragen also increases by two- to fivefold the apparent affinity of (-)-isoproterenol, ACTH, glucagon, and vasoactive intestinal polypeptide for the activation of adenylate cyclase. This effect on vasoactive intestinal polypeptide action is also seen with the enzyme of guinea pig ileal mucosa; the toxin-induced sensitivity to VIP may be relevant in the pathogenesis of cholera diarrhea. The apparent affinity of binding of 125I-labeled glucagon is increased about 1.5- to twofold in choleragen-treated liver and fat cell membranes. The effects of choleragen on the response of adenylate cyclase to hormones are independent of protein synthesis, and they are not simply a consequence to protracted stimulation of the enzyme in vivo or during preparation of the membranes. Activation of cyclase in rat erythrocytes by choleragen is not impaired by agents which disrupt microtubules or microfilaments, and it is still observed in cultured fibroblasts after completely suppressing protein synthesis with diphtheria toxin. Choleragen does not interact directly with hormone receptor sites. Simple occupation of the choleragen binding sites with the analog, choleragenoid, does not lead to any of the biological effects of the toxin.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005934:Glucagon / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D006728:Hormones / Q000494:pharmacology*; D007082:Ileum / Q000201:enzymology; D007413:Intestinal Mucosa / Q000201:enzymology; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009928:Organ Specificity; D051381:Rats; D011955:Receptors, Drug; D014734:Vibrio cholerae
D000900:Anti-Bacterial Agents; D004768:Enterotoxins; D006728:Hormones; D011955:Receptors, Drug; D006160:Guanosine Triphosphate; D000324:Adrenocorticotropic Hormone; D005934:Glucagon; D000262:Adenylyl Cyclases; D008274:Magnesium; D007545:Isoproterenol