Adenylyl Cyclase 6 Expression Is Essential for Cholera Toxin-Induced Diarrhea.
J Infect Dis
; 220(11): 1719-1728, 2019 10 22.
Article
em En
| MEDLINE
| ID: mdl-30624615
ABSTRACT
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 α-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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Adenilil Ciclases
/
Cólera
/
Toxina da Cólera
/
Diarreia
/
Células Epiteliais
Limite:
Animals
Idioma:
En
Revista:
J Infect Dis
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Dinamarca