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Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion.

ABSTRACT: Although Ca2+ signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca2+-mediated biological action.Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal Isc, which was significantly inhibited in Ca2+-free serosal solution and by several selective store-operated Ca2+ 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 Ca2+ but not cAMP, and Ca2+ 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 Ca2+ 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.Functional, biochemical and morphological experiments were performed to examine ion secretion, PI3K/Akt and CFTR activity of mouse duodenal epithelium. Ca2+ imaging was performed on HT-29 cells.Ca2+ 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 Ca2+ 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.

SUBMITTER: Yang X

PROVIDER: S-EPMC5790495 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion.

Yang Xin X Wen Guorong G Tuo Biguang B Zhang Fenglian F Wan Hanxing H He Jialin J Yang Shiming S Dong Hui H

Oncotarget 20171211 3

<h4>Background and purpose</h4>Although Ca<sup>2+</sup> signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca<sup>2+</sup>-mediated biological action.<h4>Key results</h4>Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal <i>I</i><sub>sc</sub>, which was significantly inhibited in Ca<sup>2+</sup>-free serosal solution and by several selective store-operated Ca<sup>2+</sup> channels(SOC) blocke ...[more]

PMID: 29423078

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Dataset Information

Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion.

Publications

Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion.

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