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

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

  • Front Pharmacol. 2021 Jul 14;12:684538. doi: 10.3389/fphar.2021.684538.
Yinghui Cui 1 Fenglan Chu 2 Kai Yin 2 Xiongying Chen 1 Hanxing Wan 1 Gang Luo 2 Hui Dong 1 2 Feng Xu 1
Affiliations

Affiliations

  • 1 Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China.
  • 2 Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China.
Abstract

As little is known about the role of calcium (CA2+) 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 PGE2-, 5-HT-, and CCh-induced short-circuit currents (I sc ). PGE2 (10 μM) and 5-HT (10 μM) induced mouse duodenal I sc , markedly attenuated by serosal CA2+-free solution and selective blockers of store-operated CA2+ channels on the serosal side of the duodenum. Furthermore, PGE2- and 5-HT-induced duodenal I sc was also inhibited by ER CA2+ chelator TPEN. However, dantrolene, a selective blocker of ryanodine receptors, inhibited PGE2-induced duodenal I sc , while LiCl, an inhibitor of IP3 production, inhibited 5-HT-induced I sc . Moreover, duodenal I sc response to the serosal applications of both PGE2 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 I sc via selective activation of muscarinic receptors, which was significantly inhibited in serosal CA2+-free solution but neither in mucosal CA2+-free solution nor by nifedipine. Therefore, the serosal TRPV4-constituted SOCE mechanism is likely universal for the most common and important secretagogues-induced and CA2+-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.

Keywords

5-HT; CCH; CRAC; PGE2; SOCE; TRPV4; calcium signaling.

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