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Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice.
J Physiol. 2006 Sep 01; 575(Pt 2):555-71.JP

Abstract

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.

Authors+Show Affiliations

Department of Surgery, University of California, San Francisco, Room C317, 521 Parnassus Avenue, San Francisco, CA 94143-0660, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16793902

Citation

Amadesi, Silvia, et al. "Protease-activated Receptor 2 Sensitizes TRPV1 By Protein Kinase Cepsilon- and A-dependent Mechanisms in Rats and Mice." The Journal of Physiology, vol. 575, no. Pt 2, 2006, pp. 555-71.
Amadesi S, Cottrell GS, Divino L, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J Physiol. 2006;575(Pt 2):555-71.
Amadesi, S., Cottrell, G. S., Divino, L., Chapman, K., Grady, E. F., Bautista, F., Karanjia, R., Barajas-Lopez, C., Vanner, S., Vergnolle, N., & Bunnett, N. W. (2006). Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. The Journal of Physiology, 575(Pt 2), 555-71.
Amadesi S, et al. Protease-activated Receptor 2 Sensitizes TRPV1 By Protein Kinase Cepsilon- and A-dependent Mechanisms in Rats and Mice. J Physiol. 2006 Sep 1;575(Pt 2):555-71. PubMed PMID: 16793902.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. AU - Amadesi,Silvia, AU - Cottrell,Graeme S, AU - Divino,Lorna, AU - Chapman,Kevin, AU - Grady,Eileen F, AU - Bautista,Francisco, AU - Karanjia,Rustum, AU - Barajas-Lopez,Carlos, AU - Vanner,Stephen, AU - Vergnolle,Nathalie, AU - Bunnett,Nigel W, Y1 - 2006/06/22/ PY - 2006/6/24/pubmed PY - 2006/10/27/medline PY - 2006/6/24/entrez SP - 555 EP - 71 JF - The Journal of physiology JO - J Physiol VL - 575 IS - Pt 2 N2 - 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. SN - 0022-3751 UR - https://www.unboundmedicine.com/medline/citation/16793902/Protease_activated_receptor_2_sensitizes_TRPV1_by_protein_kinase_Cepsilon__and_A_dependent_mechanisms_in_rats_and_mice_ L2 - https://doi.org/10.1113/jphysiol.2006.111534 DB - PRIME DP - Unbound Medicine ER -