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

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

  • J Mol Med (Berl). 2015 Dec;93(12):1297-309. doi: 10.1007/s00109-015-1336-5.
J Fichna 1 2 3,  D P Poole 4 5,  N Veldhuis 4,  S J MacEachern 6 7,  D Saur 8,  P K Zakrzewski 9,  A I Cygankiewicz 9,  A Mokrowiecka 10,  E Małecka-Panas 10,  W M Krajewska 9,  W Liedtke 11,  M S Steinhoff 12,  J-P Timmermans 13,  N W Bunnett 4 14,  K A Sharkey 1 6 7,  M A Storr 15 16 17
Affiliations

Affiliations

  • 1 Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.
  • 2 Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada.
  • 3 Department of Biochemistry, Medical University of Lodz, Lodz, Poland.
  • 4 Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
  • 5 Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
  • 6 Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.
  • 7 Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
  • 8 II Medizinische Klinik, Technische Universität München, Munich, Germany.
  • 9 Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
  • 10 Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
  • 11 Center for Translational Neuroscience, Duke University, Durham, NC, USA.
  • 12 Department of Dermatology and Surgery, University of California San Francisco, San Francisco, CA, USA.
  • 13 Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
  • 14 Department of Pharmacology, The University of Melbourne, Parkville, VIC, Australia.
  • 15 Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada. martin.storr@med.uni-muenchen.de.
  • 16 Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada. martin.storr@med.uni-muenchen.de.
  • 17 Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. martin.storr@med.uni-muenchen.de.
PMID: 26330151 DOI: 10.1007/s00109-015-1336-5
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 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.

Keywords

Irritable bowel syndrome; Myenteric plexus; Nitric oxide synthase type 1.

Figures
Products