Adenylyl cyclase 6 expression is essential for cholera toxin-induced diarrhea
In: The Journal of Infectious Diseases, vol 220, iss 11, 2019
Online
academicJournal
Zugriff:
BackgroundCholera 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 α-subunit activating CFTR with consequent secretory diarrhea, the AC isoform(s) involved remain unknown.MethodsWe generated intestinal epithelial cell-specific adenylyl cyclase 6 (AC6) knockout mice to study its role in CT-induced diarrhea.ResultsAC6 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.ConclusionsAC6 is a novel target for the treatment of CT-induced diarrhea.
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Adenylyl cyclase 6 expression is essential for cholera toxin-induced diarrhea
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Autor/in / Beteiligte Person: | Fenton, Robert A ; Murali, Sathish K ; Kaji, Izumi ; Akiba, Yasutada ; Kaunitz, Jonathan D ; Kristensen, Tina B ; Poulsen, Soren B ; Rieg, Jessica A Dominguez ; Rieg, Timo |
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Zeitschrift: | The Journal of Infectious Diseases, vol 220, iss 11, 2019 |
Veröffentlichung: | eScholarship, University of California, 2019 |
Medientyp: | academicJournal |
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