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

J. Fichna, D. P. Poole, N. Veldhuis, S. J. MacEachern, D. Saur, P. K. Zakrzewski, A. I. Cygankiewicz, A. Mokrowiecka, E. Małecka-Panas, W. M. Krajewska, W. Liedtke, M. S. Steinhoff, J. P. Timmermans, N. W. Bunnett, K. A. Sharkey, M. A. Storr

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: 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 Ca2+ release from enteric neurons. In conclusion, TRPV4 is involved in the regulation of GI motility in health and disease. Key messages: •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.

Original languageEnglish (US)
Pages (from-to)1297-1309
Number of pages13
JournalJournal of Molecular Medicine
Volume93
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Irritable bowel syndrome
  • Myenteric plexus
  • Nitric oxide synthase type 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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