Adenylyl cyclase 6 expression is essential for cholera toxin-induced diarrhea.

Background: Cholera toxin (CT)-induced diarrhea is mediated by cAMP-mediated active Cl - secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). Although the constitutive activation of adenylyl cyclase (AC) in response to CT is due to ADP-ribosylation of Gsα activating CFTR with consequent secretory diarrhea, the AC isoform(s) involved remain unknown.

Methods: We generated intestine epithelial cell-specific adenylyl cyclase 6 (AC6) knockout mice to study its role in cholera toxin-induced diarrhea.

Results: AC6 mRNA levels were the highest of all 9 membrane-bound AC isoforms in mouse intestinal epithelial cells. Intestinal epithelial-specific AC6 knockout mice (AC6loxloxVillinCre) had undetectable AC6 levels in small intestinal and colonic epithelial cells. No significant differences in fluid and food intake, plasma electrolytes, intestinal/colon anatomy and morphology, as well as fecal water content were observed between genotypes. Nevertheless, CT-induced fluid accumulation in vivo was completely absent in AC6loxloxVillinCre mice, associated with a lack of forskolin- and CT-induced changes in short-circuit current (Isc) of the intestinal mucosa, impaired cAMP generation in acutely isolated small intestinal epithelial cells and significantly impaired apical CFTR levels in response to forskolin.

Conclusion: AC6 is a novel target for the treatment of CT-induced diarrhea.