| First Author | Fenton RA | Year | 2019 |
| Journal | J Infect Dis | Volume | 220 |
| Issue | 11 | Pages | 1719-1728 |
| PubMed ID | 30624615 | Mgi Jnum | J:294471 |
| Mgi Id | MGI:6456504 | Doi | 10.1093/infdis/jiz013 |
| Citation | Fenton RA, et al. (2019) Adenylyl Cyclase 6 Expression Is Essential for Cholera Toxin-Induced Diarrhea. J Infect Dis 220(11):1719-1728 |
| abstractText | BACKGROUND: Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (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 adenosine diphosphate ribosylation of the small G protein alpha-subunit activating CFTR with consequent secretory diarrhea, the AC isoform(s) involved remain unknown. METHODS: We generated intestinal epithelial cell-specific adenylyl cyclase 6 (AC6) knockout mice to study its role in CT-induced diarrhea. RESULTS: AC6 messenger RNA 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, or 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 the 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. CONCLUSIONS: AC6 is a novel target for the treatment of CT-induced diarrhea. |
