Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR).
Our finding that the CFTR-AC6 protein complex is the key mediator of CTX-associated diarrhea may facilitate development of antidiarrheal agents to manage cholera symptoms and improve outcomes.
Cholera toxin (CT) causes severe diarrhea by increasing intracellular cAMP leading to a PKA-dependent increase in Cl<sup>-</sup> secretion through CFTR and decreased Na<sup>+</sup> absorption through inhibition of Na<sup>+</sup>/H<sup>+</sup> exchanger 3 (NHE3; also known as SLC9A3).
The intestinal consequences of cholera enterotoxin are caused by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel through the actions of an as-yet-unknown adenylate cyclase.
Cholera toxin or verotoxin (Shiga toxin) containing genetically inactivated (± an N-terminal polyleucine tail) A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF) mutant (5-10x), F508delCFTR Golgi maturation (<10x), cell surface expression (20x) and chloride transport (2x) in F508delCFTR transfected cells and patient-derived F508delCFTR bronchiolar epithelia, without apparent cytopathology.
Thiazolidinone CFTR inhibitors may be useful in developing large-animal models of cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas.