Transient receptor potential vanilloid 4 inhibits mouse colonic motility by activating NO-dependent enteric neurotransmission.

Published

Journal Article

Recent studies implicate TRPV4 receptors in visceral pain signaling and intestinal inflammation. Our aim was to evaluate the role of TRPV4 in the control of gastrointestinal (GI) motility and to establish the underlying mechanisms. We used immunohistochemistry and PCR to study TRPV4 expression in the GI tract. The effect of TRPV4 activation on GI motility was characterized using in vitro and in vivo motility assays. Calcium and nitric oxide (NO) imaging were performed to study the intracellular signaling pathways. Finally, TRPV4 expression was examined in the colon of healthy human subjects. We demonstrated that TRPV4 can be found on myenteric neurons of the colon and is co-localized with NO synthase (NOS-1). In vitro, the TRPV4 agonist GSK1016790A reduced colonic contractility and increased inhibitory neurotransmission. In vivo, TRPV4 activation slowed GI motility and reduced stool production in mouse models mimicking pathophysiological conditions. We also showed that TRPV4 activation inhibited GI motility by reducing NO-dependent Ca(2+) release from enteric neurons. In conclusion, TRPV4 is involved in the regulation of GI motility in health and disease.• Recent studies implicate TRPV4 in pain signaling and intestinal inflammation. • Our aim was to characterize the role of TRPV4 in the control of GI motility. • We found that TRPV4 activation reduced colonic contractility. • Our studies also showed altered TRPV4 mRNA expression in IBS-C patients. • TRPV4 may be a novel pharmacological target in functional GI diseases.

Full Text

Duke Authors

Cited Authors

  • Fichna, J; Poole, DP; Veldhuis, N; MacEachern, SJ; Saur, D; Zakrzewski, PK; Cygankiewicz, AI; Mokrowiecka, A; MaƂecka-Panas, E; Krajewska, WM; Liedtke, W; Steinhoff, MS; Timmermans, J-P; Bunnett, NW; Sharkey, KA; Storr, MA

Published Date

  • December 2015

Published In

Volume / Issue

  • 93 / 12

Start / End Page

  • 1297 - 1309

PubMed ID

  • 26330151

Pubmed Central ID

  • 26330151

Electronic International Standard Serial Number (EISSN)

  • 1432-1440

International Standard Serial Number (ISSN)

  • 0946-2716

Digital Object Identifier (DOI)

  • 10.1007/s00109-015-1336-5

Language

  • eng