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J. Biol. Chem., Vol. 275, Issue 50, 39207-39212, December 15, 2000

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A Polymorphic Protease-activated Receptor 2 (PAR2) Displaying Reduced Sensitivity to Trypsin and Differential Responses to PAR Agonists^*

Steven J. Compton^§¶, Jennifer A. Cairns, Karan-Jane Palmer, Bahjat Al-Ani^§, Morley D. Hollenberg^§, and Andrew F. Walls

From the  Immunopharmacology Group,  University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom SO16 6YD and the ^§ Endocrine Research Group, Department of Pharmacology and Therapeutics and Department of Medicine, University of Calgary, Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada

Protease-activated receptor 2 (PAR2) is a trypsin-activated member of a family of G-protein-coupled PARs. We have identified a polymorphic form of human PAR2 (PAR₂F240S) characterized by a phenylalanine to serine mutation at residue 240 within extracellular loop 2, with allelic frequencies of 0.916 (Phe²⁴⁰) and 0.084 (Ser²⁴⁰) for the wild-type and mutant alleles, respectively. Elevations in intracellular calcium were measured in permanently transfected cell lines expressing the receptors. PAR₂F240S displayed a significant reduction in sensitivity toward trypsin (~3.7-fold) and the PAR2-activating peptides, SLIGKV-NH₂ (~2.5-fold) and SLIGRL-NH₂ (~2.8-fold), but an increased sensitivity toward the selective PAR2 agonist, trans-cinnamoyl-LIGRLO-NH₂ (~4-fold). Increased sensitivity was also observed toward the selective PAR-1 agonist, TFLLR-NH₂ (~7-fold), but not to other PAR-1 agonists tested. Furthermore, we found that TLIGRL-NH₂ and a PAR4-derived peptide, trans-cinnamoyl-YPGKF-NH₂, were selective PAR₂F240S agonists. By introducing the F240S mutation into rat PAR2, we observed shifts in agonist potencies that mirrored the human PAR₂F240S, suggesting that Phe²⁴⁰ is involved in determining agonist specificity of PAR2. Finally, differences in receptor signaling were paralleled in a cell growth assay. We suggest that the distinct pharmacological profile induced by this polymorphism will have important implications for the design of PAR-targeted agonists/antagonists and may contribute to, or be predictive of, an inflammatory disease.

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