Selective Role for TRPV4 Ion Channels in Visceral Sensory Pathways

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 134; no. 7; pp. 2059 - 2069
• Main Authors: Brierley, Stuart M, Page, Amanda J, Hughes, Patrick A, Adam, Birgit, Liebregts, Tobias, Cooper, Nicole J, Holtmann, Gerald, Liedtke, Wolfgang, Blackshaw, L. Ashley
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2008
• Subjects: Afferent Pathways - metabolism; Animals; Behavior, Animal; Calcitonin Gene-Related Peptide - metabolism; Catheterization; Colon - innervation; Enteric Nervous System - metabolism; Enteric Nervous System - physiopathology; Female; Gastroenterology and Hepatology; Humans; Inflammatory Bowel Diseases - complications; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - physiopathology; Male; Mechanoreceptors - metabolism; Mechanotransduction, Cellular; Mice; Mice, Knockout; Models, Animal; Neurons, Afferent - metabolism; Pain - etiology; Pain - metabolism; Pain - physiopathology; Pain Measurement; Pain Threshold; RNA, Messenger - metabolism; Sensation; TRPV Cation Channels - deficiency; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; RR; colorectal distention; dorsal root ganglia; transient receptor potential channel, vanilloid 4; 5,6-epoxyeicosatrienoic acid; calcitonin gene-related peptide; 5,6-EET; electromyographic; transient receptor potential; TRP; analysis of variance; CRD; ANOVA; ruthenium red; TRPV4; quantitative reverse transcription–polymerase chain reaction; DRG; CTB-FITC; cholera toxin subunit B conjugated to fluorescein isothiocyanate; CGRP; EMG; QRT-PCR
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2008.01.074

Background & Aims: Although there are many candidates as molecular mechanotransducers, so far there has been no evidence for molecular specialization of visceral afferents. Here, we show that colonic afferents express a specific molecular transducer that underlies their specialized mechanosensory function: the transient receptor potential channel, vanilloid 4 (TRPV4). Methods: We found TRPV4 mRNA is highly enriched in colonic sensory neurons compared with other visceral and somatic sensory neurons. TRPV4 protein was found in colonic nerve fibers from patients with inflammatory bowel disease, and it colocalized in a subset of fibers with the sensory neuropeptide CGRP in mice. We characterized the responses of 8 subtypes of vagal, splanchnic, and pelvic mechanoreceptors. Results: Mechanosensory responses of colonic serosal and mesenteric afferents were enhanced by a TRPV4 agonist and dramatically reduced by targeted deletion of TRPV4 or by a TRP antagonist. Other subtypes of vagal and pelvic afferents, by contrast, were unaffected by these interventions. The behavioral responses to noxious colonic distention were also substantially reduced in mice lacking TRPV4. Conclusions: These data indicate that TRPV4 contributes to mechanically evoked visceral pain, with relevance to human disease. In view of its distribution in favor of specific populations of visceral afferents, we propose that TRPV4 may present a selective novel target for the reduction of visceral pain, which is an important opportunity in the absence of current treatments.