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Research ArticleCELLULAR AND MOLECULAR

Modified Proteinase-Activated Receptor-1 and -2 Derived Peptides Inhibit Proteinase-Activated Receptor-2 Activation by Trypsin

Bahjat Al-Ani, Mahmoud Saifeddine, Suranga J. Wijesuriya and Morley D. Hollenberg
Journal of Pharmacology and Experimental Therapeutics February 2002, 300 (2) 702-708; DOI: https://doi.org/10.1124/jpet.300.2.702
Bahjat Al-Ani
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Mahmoud Saifeddine
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Suranga J. Wijesuriya
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Morley D. Hollenberg
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Abstract

Trypsin activates proteinase-activated receptor-2 (PAR2) by a mechanism that involves the release of a tethered receptor-activating sequence. We have identified two peptides, FSLLRY-NH2(FSY-NH2) and LSIGRL-NH2 (LS-NH2) that block the ability of trypsin to activate PAR2 either in PAR2-expressing Kirsten virus-transformed kidney (KNRK) cell lines or in a rat aorta ring preparation. The reverse PAR2 peptide, LRGILS-NH2 (LRG-NH2) did not do so and FSY-NH2 failed to block thrombin activation of PAR1 in the aorta ring or in PAR1-expressing human embryonic kidney cells. Half-maximal inhibition (IC50) by FSY-NH2 and LS-NH2 of the activation of PAR2 by trypsin in a PAR2 KNRK calcium-signaling assay was observed at about 50 and 200 μM, respectively. In contrast, the activation of PAR2 by the PAR2-activating peptide, SLIGRL-NH2 (SL-NH2) was not inhibited by FSY-NH2, LS-NH2, or LRG-NH2. In a casein proteolysis assay, neither FSY-NH2 nor LS-NH2 inhibited the proteolytic action of trypsin on its substrate. In addition, FSY-NH2 and LS-NH2 were unable to prevent trypsin from hydrolyzing a 20-amino acid peptide, GPNSKGR/SLIGRLDTPYGGC representing the trypsin cleavage/activation site of rat PAR2. Similarly, FSY-NH2 and LS-NH2 failed to block the ability of trypsin to release the PAR2 N-terminal epitope that is cleaved from the receptor upon proteolytic activation of receptor-expressing KNRK cells. We conclude that the peptides FSY-NH2 and LS-NH2 block the ability of trypsin to activate PAR2 by a mechanism that does not involve a simple inhibition of trypsin proteolytic activity, but possibly by interacting with a tethered ligand receptor-docking site.

Footnotes

  • Supported primarily by an operating grant from the Canadian Institutes of Health Research (formerly Medical Research Council of Canada) and by ancillary support from a Kidney Foundation of Canada operating grant (to S.J.W.) and a Johnson & Johnson focused giving grant.

  • Abbreviations:
    Amino acids are abbreviated by their one-letter code
    PAR, proteinase-activated receptor
    AP
    activating peptides
    STI
    soya trypsin inhibitor
    B5
    antibody targeted to the cleavage/activation sequence (GPNSKGRSLIGRLDTP) of rat PAR2
    FSY-NH2
    FSLLRY-NH2
    HEK
    human embryonic kidney
    KNRK
    Kirsten virus-transformed rat kidney
    LRG-NH2
    LRGILS-NH2
    LS-NH2
    LSIGRL-NH2
    P20
    GPNSKGRSLIGRLDTPYGGC, peptide representing the PAR2 cleavage/activation site with a C-terminal sequence (YGGC) added for radiolabeling and protein conjugation via cysteine
    PCR
    polymerase chain reaction
    SLAW
    antibody targeted to the N-terminal epitope on PAR2, released by trypsin
    SL-NH2
    SLIGRL-NH2
    • Received August 29, 2001.
    • Accepted November 2, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 2
1 Feb 2002
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Research ArticleCELLULAR AND MOLECULAR

Modified Proteinase-Activated Receptor-1 and -2 Derived Peptides Inhibit Proteinase-Activated Receptor-2 Activation by Trypsin

Bahjat Al-Ani, Mahmoud Saifeddine, Suranga J. Wijesuriya and Morley D. Hollenberg
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 702-708; DOI: https://doi.org/10.1124/jpet.300.2.702

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Research ArticleCELLULAR AND MOLECULAR

Modified Proteinase-Activated Receptor-1 and -2 Derived Peptides Inhibit Proteinase-Activated Receptor-2 Activation by Trypsin

Bahjat Al-Ani, Mahmoud Saifeddine, Suranga J. Wijesuriya and Morley D. Hollenberg
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 702-708; DOI: https://doi.org/10.1124/jpet.300.2.702
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