caa a22 4500 605543240 CHVBK 20210128100925.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s00109-015-1336-5 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1336-5 Transient receptor potential vanilloid 4 inhibits mouse colonic motility by activating NO-dependent enteric neurotransmission [Elektronische Daten] [J. Fichna, D. Poole, N. Veldhuis, S. MacEachern, D Saur, P. Zakrzewski, A. Cygankiewicz, A. Mokrowiecka, E. Małecka-Panas, W. Krajewska, W. Liedtke, M. Steinhoff, J-P. Timmermans, N. Bunnett, K. Sharkey, M. Storr] 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. Springer-Verlag Berlin Heidelberg, 2015 Irritable bowel syndrome nationallicence Nitric oxide synthase type 1 nationallicence Myenteric plexus nationallicence 1400W : N-(3-Aminomethyl) benzylacetamidine, NOS-2 blocker nationallicence EFS : Electrical field stimulation nationallicence GFAP : Glial fibrillary acidic protein nationallicence GSK1016790A : (N-((1S)-1-{[4-((2S)-2-{[(2,4-Dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide, TRPV4 agonist nationallicence IBS : Irritable bowel syndrome nationallicence LMMP : Longitudinal muscle-myenteric plexus nationallicence NANC : Non-adrenergic, non-cholinergic nationallicence ODQ : 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one,​soluble guanylate cyclase inhibitor nationallicence PTIO : 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, NO scavenger nationallicence RN 1734 : 2,4-Dichloro-N-isopropyl-N-(2-isopropylaminoethyl)benzenesulfonamide, TRPV4 antagonist nationallicence RuR : Ruthenium red, TRPV antagonist nationallicence SB 366791 : 4′-Chloro-3-methoxycinnamanilide, selective TRPV1 antagonist nationallicence sGC : Soluble guanylate cyclase nationallicence SMTC : S-Methyl-l-thiocitrulline, NOS-1 blocker nationallicence TRPV4 : Transient receptor potential vanilloid type 4 nationallicence Fichna J. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada aut Poole D. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia aut Veldhuis N. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia aut MacEachern S. Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada aut Saur D. II Medizinische Klinik, Technische Universität München, Munich, Germany aut Zakrzewski P. Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland aut Cygankiewicz A. Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland aut Mokrowiecka A. Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland aut Małecka-Panas E. Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland aut Krajewska W. Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland aut Liedtke W. Center for Translational Neuroscience, Duke University, Durham, NC, USA aut Steinhoff M. Department of Dermatology and Surgery, University of California San Francisco, San Francisco, CA, USA aut Timmermans J-P Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium aut Bunnett N. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia aut Sharkey K. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada aut Storr M. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/12(2015-12-01), 1297-1309 0946-2716 93:12<1297 2015 93 109 https://doi.org/10.1007/s00109-015-1336-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1336-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fichna J. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada aut NATIONALLICENCE 700 1- Poole D. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia aut NATIONALLICENCE 700 1- Veldhuis N. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia aut NATIONALLICENCE 700 1- MacEachern S. Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada aut NATIONALLICENCE 700 1- Saur D. II Medizinische Klinik, Technische Universität München, Munich, Germany aut NATIONALLICENCE 700 1- Zakrzewski P. Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland aut NATIONALLICENCE 700 1- Cygankiewicz A. Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland aut NATIONALLICENCE 700 1- Mokrowiecka A. Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland aut NATIONALLICENCE 700 1- Małecka-Panas E. Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland aut NATIONALLICENCE 700 1- Krajewska W. Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland aut NATIONALLICENCE 700 1- Liedtke W. Center for Translational Neuroscience, Duke University, Durham, NC, USA aut NATIONALLICENCE 700 1- Steinhoff M. Department of Dermatology and Surgery, University of California San Francisco, San Francisco, CA, USA aut NATIONALLICENCE 700 1- Timmermans J-P Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium aut NATIONALLICENCE 700 1- Bunnett N. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia aut NATIONALLICENCE 700 1- Sharkey K. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada aut NATIONALLICENCE 700 1- Storr M. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/12(2015-12-01), 1297-1309 0946-2716 93:12<1297 2015 93 109