| First Author | Yang X | Year | 2018 |
| Journal | Oncotarget | Volume | 9 |
| Issue | 3 | Pages | 3727-3740 |
| PubMed ID | 29423078 | Mgi Jnum | J:321497 |
| Mgi Id | MGI:6850818 | Doi | 10.18632/oncotarget.23197 |
| Citation | Yang X, et al. (2018) Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion. Oncotarget 9(3):3727-3740 |
| abstractText | Background and Purpose: Although Ca(2+) signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca(2+)-mediated biological action. Key Results: Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal Isc, which was significantly inhibited in Ca(2+)-free serosal solution and by several selective store-operated Ca(2+) channels(SOC) blockers added to the serosal side of duodenal tissues. Furthermore, we found that CRAC/Orai channels may represent the molecular candidate of SOC in intestinal epithelium. CCh increased intracellular Ca(2+) but not cAMP, and Ca(2+) signaling mediated duodenal Cl(-) and HCO3(-) secretion in wild type mice but not in CFTR knockout mice. CCh induced duodenal ion secretion and stimulated PI3K/Akt activity in duodenal epithelium, all of which were inhibited by selective PI3K inhibitors with different structures. CCh-induced Ca(2+) signaling also stimulated the phosphorylation of CFTR proteins and their trafficking to the plasma membrane of duodenal epithelial cells, which were inhibited again by selective PI3K inhibitors. Materials and Methods: Functional, biochemical and morphological experiments were performed to examine ion secretion, PI3K/Akt and CFTR activity of mouse duodenal epithelium. Ca(2+) imaging was performed on HT-29 cells. Conclusions and Implications: Ca(2+) signaling plays a critical role in intestinal ion secretion via CRAC/Orai-mediated SOCE mechanism on the serosal side of epithelium. We also demonstrated the molecular mechanisms of Ca(2+) signaling in CFTR-mediated secretion via novel PI3K/Akt pathway. Our findings suggest new perspectives for drug targets to protect the upper GI tract and control liquid homeostasis in the small intestine. |
