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

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 93; no. 12; pp. 1297 - 1309
• Main Authors: Fichna, J., Poole, D. P., Veldhuis, N., MacEachern, S. J., Saur, D, Zakrzewski, P. K., Cygankiewicz, A. I., Mokrowiecka, A., Małecka-Panas, E., Krajewska, W. M., Liedtke, W., Steinhoff, M. S., Timmermans, J-P., Bunnett, N. W., Sharkey, K. A., Storr, M. A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2015; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Colon - drug effects; Colon - physiology; Colon - physiopathology; Disease Models, Animal; Female; Gastrointestinal Motility - drug effects; Gastrointestinal Motility - genetics; Gene Expression; Guanylate Cyclase - metabolism; Human Genetics; Humans; Internal Medicine; Irritable Bowel Syndrome - drug therapy; Irritable Bowel Syndrome - genetics; Irritable Bowel Syndrome - metabolism; Irritable Bowel Syndrome - physiopathology; Leucine - analogs & derivatives; Leucine - pharmacology; Male; Mice; Mice, Knockout; Middle Aged; Models, Biological; Molecular Medicine; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Myenteric Plexus - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Original Article; Sulfonamides - pharmacology; Synaptic Transmission - genetics; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; Myenteric plexus; Nitric oxide synthase type 1; Irritable bowel syndrome
• ISSN: 0946-2716; 1432-1440; 1432-1440
• DOI: 10.1007/s00109-015-1336-5

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. 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.