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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3279    most recent 00519.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saifeddine, M. Articles by Hollenberg, M. D. Search for Related Content PubMed PubMed Citation Articles by Saifeddine, M. Articles by Hollenberg, M. D.

Proteinase-activated receptor-2 activating peptides: distinct canine coronary artery receptor systems

¹Endocrine-Diabetes Group and ²Inflammation Research Network, Departments of ³Pharmacology and Therapeutics, ⁴Physiology and Biophysics, and ⁵Medicine, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada; ⁶Respiratory Medicine, Division of Academic Medicine, University of Hull, Hull, United Kingdom; and ⁷Division of Angiology, Institut de Recherches Servier, Suresnes, France

Submitted 30 April 2007 ; accepted in final form 28 August 2007

In canine coronary artery preparations, the proteinase-activated receptor-2 (PAR₂) activating peptides (PAR₂-APs) SLIGRL-NH₂ and 2-furoyl-LIGRLO-NH₂ caused both an endothelium-dependent relaxation and an endothelium-independent contraction. Relaxation was caused at peptide concentrations 10-fold lower than those causing a contractile response. Although trans-cinnamoyl-LIGRLO-NH₂, like other PAR₂-APs, caused relaxation, it was inactive as a contractile agonist and instead antagonized the contractile response to SLIGRL-NH₂. RT-PCR-based sequencing of canine PAR₂ revealed a cleavage/activation (indicated by underlines) sequence (SKGR/SLIGKTDSSLQITGKG) that is very similar to the human PAR₂ sequence (R/SLIGKV). As a synthetic peptide, the canine PAR-AP (SLIGKT-NH₂) was a much less potent agonist than either SLIGRL-NH₂ or 2-furoyl-LIGRLO-NH₂, either in the coronary contractile assay or in a Madin-Darby canine kidney (MDCK) cell PAR₂ calcium signaling assay. In the MDCK signaling assay, the order of potencies was as follows: 2-furoyl-LIGRLO-NH₂ >> SLIGRL-NH₂ = trans-cinnamoyl-LIGRLO-NH₂ >> SLIGKT-NH₂, as expected for PAR₂ responses. In the coronary contractile assay, however, the order of potencies was very different: SLIGRL-NH₂ >> 2-furoyl-LIGRLO-NH₂ >> SLIGKT-NH₂, trans-cinnamoyl-LIGRLO-NH₂ = antagonist. Because of 1) the distinct agonist (relaxant) and antagonist (contractile) activity of trans-cinnamoyl-LIGRLO-NH₂ in the canine coronary contractile assays, 2) the different concentration ranges over which the peptides caused either relaxation or contraction in the same coronary preparation, and 3) the markedly distinct structure-activity profiles for the PAR-APs in the coronary contractile assay, compared with those for PAR₂-mediated MDCK cell calcium signaling, we suggest that the canine coronary tissue possesses a receptor system for the PAR-APs that is distinct from PAR₂ itself.

protease; vascular G protein-coupled receptor