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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Proteinase-Activated Receptor (PAR)-1 and -2 Agonists Induce Mediator Release from Mast Cells by Pathways Distinct from PAR-1 and PAR-2

Grant R. Stenton, Osamu Nohara, René E. Déry, Harissios Vliagoftis, Mark Gilchrist, Ankur Johri, John L. Wallace, Morley D. Hollenberg, Redwan Moqbel and A. Dean Befus
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 466-474; DOI: https://doi.org/10.1124/jpet.302.2.466
Grant R. Stenton
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Osamu Nohara
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René E. Déry
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Harissios Vliagoftis
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Mark Gilchrist
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Ankur Johri
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John L. Wallace
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Morley D. Hollenberg
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Redwan Moqbel
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A. Dean Befus
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Abstract

Because thrombin-induced inflammation is partially mast cell-dependent and involves proteinase-activated receptors (PARs), we hypothesized that mast cells express PAR and can be stimulated with PAR-activating peptides (PAR-AP). We demonstrated that rat peritoneal mast cells expressed PAR-1 and PAR-2 mRNA, and that PAR-2AP (tc-LIGRLO-NH2, 1 μM) induced 64.2 ± 4.4% specific β-hexosaminidase release from peritoneal mast cells, whereas another PAR-2AP (SLIGRL-NH2, 10 μM), trypsin (40 U/ml), and mast cell tryptase (1.5 μg/ml) did not. PAR-1AP (ApfFRChaCitY-NH2, 10 μM) (Cit) induced 11.7 ± 3.7% specific β-hexosaminidase release, whereas another PAR-1AP (TFLLR-NH2, 40 μM) and human thrombin (10 U/ml) did not. PAR-AP, tc-LIGRLO-NH2, and Cit increased the free intracellular Ca2+ concentration, whereas trypsin, tryptase, thrombin, and other PAR-APs did not. Desensitization of Ca2+ flux with different agonists suggests that although tc-LIGRLO-NH2, Cit, and compound 48/80 have similar mechanisms of action, tc-LIGRLO-NH2 also activates mast cells by a mechanism distinct from that of 48/80. Using benzalkonium chloride, which antagonizes the actions of 48/80 by competing for the same Gi protein, we determined that benzalkonium chloride suppressed tc-LIGRLO-NH2-mediated (0.1 μM) β-hexosaminidase release by 62%. Moreover, removal of sialic acid from peritoneal mast cells, using neuraminidase (2 U/ml), inhibited Cit- (10 μM, 52%) and tc-LIGRLO-NH2 (0.5 μM, 29%)-mediated β-hexosaminidase release. Thus, tc-LIGRLO-NH2 and Cit have at least partially similar mechanisms of action as 48/80. PAR-AP may therefore activate mast cells via multiple mechanisms that are distinct from those of classical PAR-1 and PAR-2. The responsiveness of mast cells to PAR-AP via a non-PAR-1/non-PAR-2 mechanism complicates the interpretation of in vivo studies using these peptides.

Footnotes

  • This work was supported by funds from the Canadian Institutes for Health Research (to A.D.B. and M.D.H.) and a Postdoctoral Fellowship from the Canadian Lung Association/Medical Research Council of Canada/GlaxoWellcome (to G.R.S.). A.D.B. is the holder of the AstraZeneca Canada, Inc. (Chair in Asthma Research); J.L.W. is an Alberta Heritage Foundation for Medical Research Scientist and a Canadian Institutes for Health Research Senior Scientist; R.M. is an Alberta Heritage Foundation for Medical Research Senior Scholar; and H.V. is a Canadian Institutes for Health Research Scholar and an Alberta Heritage Foundation for Medical Research Clinical Investigator.

  • Abbreviations:
    PAR
    proteinase-activated receptor
    PAR-AP
    proteinase-activated receptor-activating peptide
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    HEK
    human embryonic kidney
    PBS
    phosphate-buffered saline
    HTB
    HEPES-Tyrode's buffer
    RT-PCR
    reverse transcription-polymerase chain reaction
    bp
    base pair(s)
    [Ca2+]i
    free intracellular calcium concentration
    Cit
    ApfFRChaCitY-NH2
    • Received December 18, 2001.
    • Accepted April 9, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Proteinase-Activated Receptor (PAR)-1 and -2 Agonists Induce Mediator Release from Mast Cells by Pathways Distinct from PAR-1 and PAR-2

Grant R. Stenton, Osamu Nohara, René E. Déry, Harissios Vliagoftis, Mark Gilchrist, Ankur Johri, John L. Wallace, Morley D. Hollenberg, Redwan Moqbel and A. Dean Befus
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 466-474; DOI: https://doi.org/10.1124/jpet.302.2.466

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Proteinase-Activated Receptor (PAR)-1 and -2 Agonists Induce Mediator Release from Mast Cells by Pathways Distinct from PAR-1 and PAR-2

Grant R. Stenton, Osamu Nohara, René E. Déry, Harissios Vliagoftis, Mark Gilchrist, Ankur Johri, John L. Wallace, Morley D. Hollenberg, Redwan Moqbel and A. Dean Befus
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 466-474; DOI: https://doi.org/10.1124/jpet.302.2.466
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