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Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice

Grant, A. D., Cottrell, G. S., Amadesi, S., Trevisani, M., Nicoletti, P., Materazzi, S., Altier, C., Cenac, N., Zamponi, G. W., Bautista-Cruz, F., Lopez, C. B., Joseph, E. K., Levine, J. D., Liedtke, W., Vanner, S., Vergnolle, N., Geppetti, P. and Bunnett, N. W. (2007) Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. Journal of Physiology, 578 (3). pp. 715-733. ISSN 0022-3751

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To link to this item DOI: 10.1113/jphysiol.2006.121111

Abstract/Summary

Exacerbated sensitivity to mechanical stimuli that are normally innocuous or mildly painful (mechanical allodynia and hyperalgesia) occurs during inflammation and underlies painful diseases. Proteases that are generated during inflammation and disease cleave protease-activated receptor 2 (PAR2) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR2-mediated mechanical hyperalgesia requires sensitization of the ion channel transient receptor potential vanilloid 4 (TRPV4). Immunoreactive TRPV4 was coexpressed by rat dorsal root ganglia (DRG) neurons with PAR2, substance P (SP) and calcitonin gene-related peptide (CGRP), mediators of pain transmission. In PAR2-expressing cell lines that either naturally expressed TRPV4 (bronchial epithelial cells) or that were transfected to express TRPV4 (HEK cells), pretreatment with a PAR2 agonist enhanced Ca2+ and current responses to the TRPV4 agonists phorbol ester 4alpha-phorbol 12,13-didecanoate (4alphaPDD) and hypotonic solutions. PAR2-agonist similarly sensitized TRPV4 Ca2+ signals and currents in DRG neurons. Antagonists of phospholipase Cbeta and protein kinases A, C and D inhibited PAR2-induced sensitization of TRPV4 Ca2+ signals and currents. 4alphaPDD and hypotonic solutions stimulated SP and CGRP release from dorsal horn of rat spinal cord, and pretreatment with PAR2 agonist sensitized TRPV4-dependent peptide release. Intraplantar injection of PAR2 agonist caused mechanical hyperalgesia in mice and sensitized pain responses to the TRPV4 agonists 4alphaPDD and hypotonic solutions. Deletion of TRPV4 prevented PAR2 agonist-induced mechanical hyperalgesia and sensitization. This novel mechanism, by which PAR2 activates a second messenger to sensitize TRPV4-dependent release of nociceptive peptides and induce mechanical hyperalgesia, may underlie inflammatory hyperalgesia in diseases where proteases are activated and released.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30269
Uncontrolled Keywords:Animals Calcitonin Gene-Related Peptide/metabolism Calcium Signaling/physiology Cell Line Cells, Cultured Epithelial Cells/metabolism Ganglia, Spinal/metabolism Humans Hyperalgesia/metabolism/*physiopathology Male Mice Mice, Inbred C57BL Mice, Knockout Nociceptors/physiology Pain/physiopathology Peptides/metabolism Rats Rats, Sprague-Dawley Receptor, PAR-2/genetics/*metabolism Substance P/metabolism TRPV Cation Channels/genetics/*metabolism
Additional Information:Grant, Andrew D Cottrell, Graeme S Amadesi, Silvia Trevisani, Marcello Nicoletti, Paola Materazzi, Serena Altier, Christophe Cenac, Nicolas Zamponi, Gerald W Bautista-Cruz, Francisco Lopez, Carlos Barajas Joseph, Elizabeth K Levine, Jon D Liedtke, Wolfgang Vanner, Stephen Vergnolle, Nathalie Geppetti, Pierangelo Bunnett, Nigel W DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ DK57840/DK/NIDDK NIH HHS/ Wellcome Trust/United Kingdom England J Physiol. 2007 Feb 1;578(Pt 3):715-33. Epub 2006 Nov 23.
Publisher:Wiley-Blackwell

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