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Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice

Amadesi, S., Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, Divino, L., Chapman, K., Grady, E. F., Bautista, F., Karanjia, R., Barajas-Lopez, C., Vanner, S., Vergnolle, N. and Bunnett, N. W. (2006) Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. Journal of Physiology, 575 (2). pp. 555-571. ISSN 0022-3751

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To link to this item DOI: 10.1113/jphysiol.2006.111534

Abstract/Summary

Proteases that are released during inflammation and injury cleave protease-activated receptor 2 (PAR2) on primary afferent neurons to cause neurogenic inflammation and hyperalgesia. PAR2-induced thermal hyperalgesia depends on sensitization of transient receptor potential vanilloid receptor 1 (TRPV1), which is gated by capsaicin, protons and noxious heat. However, the signalling mechanisms by which PAR2 sensitizes TRPV1 are not fully characterized. Using immunofluorescence and confocal microscopy, we observed that PAR2 was colocalized with protein kinase (PK) Cepsilon and PKA in a subset of dorsal root ganglia neurons in rats, and that PAR2 agonists promoted translocation of PKCepsilon and PKA catalytic subunits from the cytosol to the plasma membrane of cultured neurons and HEK 293 cells. Subcellular fractionation and Western blotting confirmed this redistribution of kinases, which is indicative of activation. Although PAR2 couples to phospholipase Cbeta, leading to stimulation of PKC, we also observed that PAR2 agonists increased cAMP generation in neurons and HEK 293 cells, which would activate PKA. PAR2 agonists enhanced capsaicin-stimulated increases in [Ca2+]i and whole-cell currents in HEK 293 cells, indicating TRPV1 sensitization. The combined intraplantar injection of non-algesic doses of PAR2 agonist and capsaicin decreased the latency of paw withdrawal to radiant heat in mice, indicative of thermal hyperalgesia. Antagonists of PKCepsilon and PKA prevented sensitization of TRPV1 Ca2+ signals and currents in HEK 293 cells, and suppressed thermal hyperalgesia in mice. Thus, PAR2 activates PKCepsilon and PKA in sensory neurons, and thereby sensitizes TRPV1 to cause thermal hyperalgesia. These mechanisms may underlie inflammatory pain, where multiple proteases are generated and released.

Item Type:Article
Refereed:Yes
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30276
Uncontrolled Keywords:Animals Calcium Signaling/physiology Capsaicin/pharmacology Cell Line Cells, Cultured Cyclic AMP-Dependent Protein Kinases/genetics/metabolism/*physiology Electrophysiology Enzyme Activation/drug effects/physiology Ganglia, Spinal/cytology/metabolism Gene Expression Regulation, Enzymologic/physiology Humans Hyperalgesia/physiopathology Male Mice Mice, Inbred C57BL Neurons, Afferent/cytology/metabolism Protein Kinase C-epsilon/genetics/metabolism/*physiology Rats Rats, Sprague-Dawley Receptor, PAR-2/agonists/antagonists & inhibitors/*physiology TRPV Cation Channels/*physiology
Publisher:Wiley-Blackwell

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