Role of Serosal TRPV4-Constituted SOCE Mechanism in Secretagogues-Stimulated Intestinal Epithelial Anion Secretion.

As little is known about the role of calcium (Ca) signaling mediating the small intestinal epithelial anion secretion, we aimed to study its regulatory role in secretagogue-stimulated duodenal anion secretion and the underlying molecular mechanisms. Therefore, intestinal anion secretion from native mouse duodenal epithelia was examined with Ussing chambers to monitor PGE-, 5-HT-, and CCh-induced short-circuit currents ( ). PGE (10 μM) and 5-HT (10 μM) induced mouse duodenal , markedly attenuated by serosal Ca-free solution and selective blockers of store-operated Ca channels on the serosal side of the duodenum. Furthermore, PGE- and 5-HT-induced duodenal was also inhibited by ER Ca chelator TPEN. However, dantrolene, a selective blocker of ryanodine receptors, inhibited PGE-induced duodenal , while LiCl, an inhibitor of IP production, inhibited 5-HT-induced . Moreover, duodenal response to the serosal applications of both PGE and 5-HT was significantly attenuated in transient receptor potential vanilloid 4 (TRPV4) knockout mice. Finally, mucosal application of carbachol (100 μM) also induced duodenal via selective activation of muscarinic receptors, which was significantly inhibited in serosal Ca-free solution but neither in mucosal Ca-free solution nor by nifedipine. Therefore, the serosal TRPV4-constituted SOCE mechanism is likely universal for the most common and important secretagogues-induced and Ca-dependent intestinal anion secretion. These findings will enhance our knowledge about gastrointestinal (G.I.) epithelial physiology and the associated G.I. diseases, such as diarrhea and constipation.