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

Simple item page
dc.contributor.authorGrant, Andrew Douglas
dc.contributor.authorCottrell, Graeme S.
dc.contributor.authorAmadesi, Silva
dc.contributor.authorTrevisani, Marcello
dc.contributor.authorNicoletti, Paola
dc.contributor.authorMaterazzi, Serena
dc.contributor.authorAltier, Christophe
dc.contributor.authorCenac, Nicolas S.
dc.contributor.authorZamponi, Gerald W.
dc.contributor.authorBautista-Cruz, Francisco
dc.contributor.authorLopez, Carlos Barajas
dc.contributor.authorJoseph, Elizabeth K.
dc.contributor.authorLevine, Jon David
dc.contributor.authorLiedtke, Wolfgang B.
dc.contributor.authorVanner, Stephen J.
dc.contributor.authorVergnolle, Nathalie
dc.contributor.authorGeppetti, Pierangelo
dc.contributor.authorBunnett, Nigel W.
dc.date.accessioned2018-06-07T19:28:39Z
dc.date.available2018-06-07T19:28:39Z
dc.date.issued2006-11-23
dc.description.abstractExacerbated 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.en_US
dc.identifier.citationGrant, A. D., Cottrell, G. S., Amadesi, S., Trevisani, M., Nicoletti, P., Materazzi, S., … 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), 715–733. https://doi.org/10.1113/jphysiol.2006.121111en_US
dc.identifier.doihttp://dx.doi.org/10.1113/jphysiol.2006.121111en_US
dc.identifier.issn0022-3751
dc.identifier.urihttp://hdl.handle.net/1880/106735
dc.identifier.urihttps://doi.org/10.11575/PRISM/43728
dc.language.isoenen_US
dc.publisherBlackwell Publishingen_US
dc.publisher.departmentPhysiology & Pharmacologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.publisher.policyhttp://olabout.wiley.com/WileyCDA/Section/id-826716.htmlen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.titleProtease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in miceen_US
dc.typejournal articleen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Grant_JPhys2007_reprint.pdf
Size:
805.3 KB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.92 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Cumming School of Medicine Research & Publications