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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/C503    most recent 00460.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tuo, B. Articles by Dong, H. PubMed PubMed Citation Articles by Tuo, B. Articles by Dong, H.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Involvement of phosphatidylinositol 3-kinase in cAMP- and cGMP-induced duodenal epithelial CFTR activation in mice

¹Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi, China; and ²Department of Medicine, School of Medicine, University of Californian, San Diego, California

Submitted 8 September 2008 ; accepted in final form 15 June 2009

Although phosphatidylinositol 3-kinase (PI3K) is essential for several cellular signal transductions, its role in the regulation of cystic fibrosis transmembrane conductance regulator (CFTR) activity in intestinal epithelial cells is poorly understood. Therefore, the possible involvement of PI3K in the regulation of cAMP- and cGMP-induced duodenal epithelial CFTR activation was investigated in the present study. Forskolin and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) markedly stimulated duodenal mucosal HCO secretion and short-circuit current (I_sc) in CFTR wild-type mice, which was significantly inhibited by CFTR_inh-172, a highly potent and specific CFTR inhibitor. Forskolin and 8-Br-cGMP failed to stimulate duodenal HCO secretion and I_sc in CFTR knockout mice. Moreover, forskolin- and 8-Br-cGMP-stimulated duodenal HCO secretion and I_sc were significantly reduced by wortmannin and LY294002, two selective PI3K inhibitors that are structurally and mechanistically different. Forskolin and 8-Br-cGMP induced CFTR phosphorylation and shifted CFTR proteins to the plasma membrane of duodenal epithelial cells, which were inhibited by wortmannin and LY294002. Forskolin and 8-Br-cGMP not only increased the activity of PI3K but also induced the phosphorylation of Akt, a signaling molecule downstream of PI3K, which were again inhibited by wortmannin and LY294002. Together, our results obtained from functional, biochemical, and morphological studies demonstrate that PI3K pathway plays an important role in the regulation of cAMP- and cGMP-induced duodenal epithelial CFTR channel activity and intracellular trafficking.

cystic fibrosis transmembrane conductance regulator; phosphatidylinositol 3-kinase; duodenal epithelial cell; adenosine 3',5'-cyclic monophosphate; guanosine 3',5'-cyclic monophosphate