AUTHOR=Cui Yinghui , Chu Fenglan , Yin Kai , Chen Xiongying , Wan Hanxing , Luo Gang , Dong Hui , Xu Feng 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.684538

DOI=10.3389/fphar.2021.684538

ISSN=1663-9812

ABSTRACT=<p>As little is known about the role of calcium (Ca<sup>2+</sup>) 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<sub>2</sub>-, 5-HT-, and CCh-induced short-circuit currents (<italic>I</italic><sub><italic>sc</italic></sub>). PGE<sub>2</sub> (10 μM) and 5-HT (10 μM) induced mouse duodenal <italic>I</italic><sub><italic>sc</italic></sub>, markedly attenuated by serosal Ca<sup>2+</sup>-free solution and selective blockers of store-operated Ca<sup>2+</sup> channels on the serosal side of the duodenum. Furthermore, PGE<sub>2</sub>- and 5-HT-induced duodenal <italic>I</italic><sub><italic>sc</italic></sub> was also inhibited by ER Ca<sup>2+</sup> chelator TPEN. However, dantrolene, a selective blocker of ryanodine receptors, inhibited PGE<sub>2</sub>-induced duodenal <italic>I</italic><sub><italic>sc</italic></sub>, while LiCl, an inhibitor of IP<sub>3</sub> production, inhibited 5-HT-induced <italic>I</italic><sub><italic>sc</italic></sub>. Moreover, duodenal <italic>I</italic><sub><italic>sc</italic></sub> response to the serosal applications of both PGE<sub>2</sub> 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 <italic>I</italic><sub><italic>sc</italic></sub> via selective activation of muscarinic receptors, which was significantly inhibited in serosal Ca<sup>2+</sup>-free solution but neither in mucosal Ca<sup>2+</sup>-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<sup>2+</sup>-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.</p>