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Vol. 288, Issue 1, 358-370, January 1999
Endocrine Research Group (A.K., M.S., B.A-A., M.D.H.),
Department
of Pharmacology and Therapeutics (M.D.H.) and
Department of
Medicine (M.D.H.), The University of Calgary, Faculty of Medicine,
Calgary, Alberta, Canada; and
BioChem Therapeutic Inc. (L.L.), Laval,
Quebec, Canada
We developed a calcium signaling-based assay, using cultured human
embryonic kidney cells (HEK), that evaluates simultaneously, the
activation/desensitization or blockade of the proteinase-activated receptors, PAR1 and PAR2. Using this assay, we
analyzed the actions of a number of previously described putative
PAR1-targeted peptide agonists and antagonists. We found
that most of the previously described PAR1-targeted agents
can also activate/desensitize PAR2, and most of these
peptides can also activate a calcium signaling pathway in a target cell
that possesses PAR2 along with PAR1. Furthermore, we used this assay to develop a PAR1
receptor-activating probe
[Ala-parafluoroPhe-Arg-Cha-Cit-Tyr-NH2
(Cit-NH2)], which displays a high degree of specificity
for PAR1 over PAR2, and we used the assay to
quantitate the ability of trypsin to disarm the activation of
PAR1 by thrombin. The abilities of the
PAR1-targeted agents to desensitize or block
PAR1 in the HEK cell assay were compared with their
activities in a human platelet aggregation assay. Our data illustrate
the usefulness of the HEK cell assay for evaluating the
PAR1/PAR2 selectivity of PAR-activating
agonists. The PAR1-selective agonist that we developed
using the assay should prove useful for studying the effects of
selectively activating PAR1 in vivo.
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G. R. Stenton, O. Nohara, R. E. Dery, H. Vliagoftis, M. Gilchrist, A. Johri, J. L. Wallace, M. D. Hollenberg, R. Moqbel, and A. D. Befus Proteinase-Activated Receptor (PAR)-1 and -2 Agonists Induce Mediator Release from Mast Cells by Pathways Distinct from PAR-1 and PAR-2 J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 466 - 474. [Abstract] [Full Text] [PDF]
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B. Al-Ani, M. Saifeddine, S. J. Wijesuriya, and M. D. Hollenberg Modified Proteinase-Activated Receptor-1 and -2 Derived Peptides Inhibit Proteinase-Activated Receptor-2 Activation by Trypsin J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 702 - 708. [Abstract] [Full Text] [PDF]
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S. Fiorucci, A. Mencarelli, B. Palazzetti, E. Distrutti, N. Vergnolle, M. D. Hollenberg, J. L. Wallace, A. Morelli, and G. Cirino Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis PNAS, November 20, 2001; 98(24): 13936 - 13941. [Abstract] [Full Text] [PDF]
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M. C. Buresi, E. Schleihauf, N. Vergnolle, A. Buret, J. L. Wallace, M. D. Hollenberg, and W. K. MacNaughton Protease-activated receptor-1 stimulates Ca2+-dependent Cl{-} secretion in human intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, August 1, 2001; 281(2): G323 - G332. [Abstract] [Full Text] [PDF]
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S. R. Macfarlane, M. J. Seatter, T. Kanke, G. D. Hunter, and R. Plevin Proteinase-Activated Receptors Pharmacol. Rev., June 1, 2001; 53(2): 245 - 282. [Abstract] [Full Text] [PDF]
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H. Danahay, L. Withey, C. T. Poll, S. F. J. van de Graaf, and R. J. Bridges Protease-activated receptor-2-mediated inhibition of ion transport in human bronchial epithelial cells Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1455 - C1464. [Abstract] [Full Text] [PDF]
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M. D. Hollenberg Receptor Binding and Agonist Efficacy: New Insights from Mutants of the Thrombin Protease-Activated Receptor-1 (PAR-1) Mol. Pharmacol., April 13, 2001; 58(6): 1175 - 1177. [Full Text]
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B. D. Blackhart, L. Ruslim-Litrus, C.-C. Lu, V. L. Alves, W. Teng, R. M. Scarborough, E. E. Reynolds, and D. Oksenberg Extracellular Mutations of Protease-Activated Receptor-1 Result in Differential Activation by Thrombin and Thrombin Receptor Agonist Peptide Mol. Pharmacol., April 13, 2001; 58(6): 1178 - 1187. [Abstract] [Full Text]
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P. J. O'Brien, N. Prevost, M. Molino, M. K. Hollinger, M. J. Woolkalis, D. S. Woulfe, and L. F. Brass Thrombin Responses in Human Endothelial Cells. CONTRIBUTIONS FROM RECEPTORS OTHER THAN PAR1 INCLUDE THE TRANSACTIVATION OF PAR2 BY THROMBIN-CLEAVED PAR1 J. Biol. Chem., April 28, 2000; 275(18): 13502 - 13509. [Abstract] [Full Text] [PDF]
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B. Al-Ani, M. Saifeddine, A. Kawabata, B. Renaux, S. Mokashi, and M. D. Hollenberg Proteinase-Activated Receptor 2 (PAR2): Development of a Ligand-Binding Assay Correlating with Activation of PAR2 by PAR1- and PAR2-Derived Peptide Ligands J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 753 - 760. [Abstract] [Full Text]
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S. J. Compton, J. A. Cairns, K.-J. Palmer, B. Al-Ani, M. D. Hollenberg, and A. F. Walls A Polymorphic Protease-activated Receptor 2 (PAR2) Displaying Reduced Sensitivity to Trypsin and Differential Responses to PAR Agonists J. Biol. Chem., December 8, 2000; 275(50): 39207 - 39212. [Abstract] [Full Text] [PDF]
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J. R. Hamilton, A. G. Frauman, and T. M. Cocks Increased Expression of Protease-Activated Receptor-2 (PAR2) and PAR4 in Human Coronary Artery by Inflammatory Stimuli Unveils Endothelium-Dependent Relaxations to PAR2 and PAR4 Agonists Circ. Res., July 6, 2001; 89(1): 92 - 98. [Abstract] [Full Text] [PDF]
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