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Vol. 302, Issue 2, 466-474, August 2002

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

Glaxo-Heritage Asthma Research Laboratory, Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (G.R.S., O.N., R.E.D., H.V., M.G., A.J., R.M., A.D.B.); and Department of Pharmacology and Experimental Therapeutics, University of Calgary, Calgary, Alberta, Canada (J.L.W., M.D.H.)

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 beta -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 beta -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) beta -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 beta -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.

0022-3565/02/3022-0466$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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