cAMP is a second messenger that regulates many diverse cellular functions. In th

Question

cAMP is a second messenger that regulates many diverse cellular functions. In the intestinal lumen, cAMP is responsible for maintaining electrolyte and water balance. Certain bacterial toxins, including one produced by Vibrio cholera, can upset the levels of cAMP, leading to fatal dehydration.

(A) Given what you know about the mechanism of Vibrio cholera toxin, describe how intracellular cAMP concentration would change, as a function of time, for (1) normal intestinal epithelial cells treated with a GPCR agonist to activate G?s, as compared with (2) cholera-toxin treated cells stimulated with the same GPCR agonist. Explain your conclusions.

(B) Would you expect lower or higher levels of activated PKA in cells treated with cholera toxin (as compared to the control cells), and why? How does this explain the "fatal dehydration" that can occur due to cholera toxin?

Explanation / Answer

A) The ADP-ribosylation causes the G?s subunit to lose its catalytic activity in hydrolyzing GTP to GDP + Pi so it remains activated longer than normal. Increased G?s activation leads to increased adenylate cyclase activity, which increases the intracellular concentration of cAMP to more than 100-fold over normal and over-activates cytosolic PKA. These active PKA then phosphorylate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel proteins, which leads to ATP-mediated efflux of chloride ions and leads to secretion of H2O, Na+, K+, and HCO3? into the intestinal lumen. In addition, the entry of Na+ and consequently the entry of water into enterocytes are diminished. The combined effects result in rapid fluid loss from the intestine, up to 2 liters per hour, leading to severe dehydration and other factors associated with cholera, including a rice-water stool.

B) Lower level of PKA.

Cholera is an infection of the small intestine caused by the bacterium Vibrio cholerae. Watery diarrhea and vomiting result from such an infection which can even lead to fatal dehydration. Eating food or water contaminated by the feces of an infected person in a cholera risk zone is the source of infection.

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