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


CONCLUSIONS
• 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.
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.|Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada.|Department of Biochemistry, Medical University of Lodz, Lodz, Poland.
J
J
Fichna
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.|Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
D P
DP
Poole
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
N
N
Veldhuis
Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.|Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
S J
SJ
MacEachern
II Medizinische Klinik, Technische Universität München, Munich, Germany.
D
D
Saur
Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
P K
PK
Zakrzewski
Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
A I
AI
Cygankiewicz
Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
A
A
Mokrowiecka
Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
E
E
Małecka-Panas
Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
W M
WM
Krajewska
Center for Translational Neuroscience, Duke University, Durham, NC, USA.
W
W
Liedtke
Department of Dermatology and Surgery, University of California San Francisco, San Francisco, CA, USA.
M S
MS
Steinhoff
Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
J-P
JP
Timmermans
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.|Department of Pharmacology, The University of Melbourne, Parkville, VIC, Australia.
N W
NW
Bunnett
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.|Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.|Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
K A
KA
Sharkey
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada. martin.storr@med.uni-muenchen.de.|Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada. martin.storr@med.uni-muenchen.de.|Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. martin.storr@med.uni-muenchen.de.
M A
MA
Storr
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D003106:Colon / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009197:Myenteric Plexus / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000235:genetics*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D013449:Sulfonamides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D007930:Leucine
Irritable bowel syndrome; Myenteric plexus; Nitric oxide synthase type 1