Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 172, Issue 18, Pages 4535-4545Publisher
WILEY
DOI: 10.1111/bph.13238
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Funding
- National Institutes of Health [NS 073664, R01NS 065926, R01AI083403, ES 04940]
- National Institute of Health training grant [T32 HL 007249, T32 ES 007091, R25 GM 062584]
- State of Arizona Technology and Research Initiative Fund through Bio5
- State of Arizona Technology and Research Initiative Fund through Water Sustainability Program
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Background and Purpose Proteinase-activated receptor-2 (PAR2) is a GPCR linked to diverse pathologies, including acute and chronic pain. PAR2 is one of the four PARs that are activated by proteolytic cleavage of the extracellular amino terminus, resulting in an exposed, tethered peptide agonist. Several peptide and peptidomimetic agonists, with high potency and efficacy, have been developed to probe the functions of PAR2, in vitro and in vivo. However, few similarly potent and effective antagonists have been described. Experimental Approach We modified the peptidomimetic PAR2 agonist, 2-furoyl-LIGRLO-NH2, to create a novel PAR2 peptidomimetic ligand, C391. C391 was evaluated for PAR2 agonist/antagonist activity to PAR2 across G(q) signalling pathways using the naturally expressing PAR2 cell line 16HBE14o-. For antagonist studies, a highly potent and specific peptidomimetic agonist (2-aminothiazo-4-yl-LIGRL-NH2) and proteinase agonist (trypsin) were used to activate PAR2. C391 was also evaluated in vivo for reduction of thermal hyperalgesia, mediated by mast cell degranulation, in mice. Key Results C391 is a potent and specific peptidomimetic antagonist, blocking multiple signalling pathways (G(q)-dependent Ca2+, MAPK) induced following peptidomimetic or proteinase activation of human PAR2. In a PAR2-dependent behavioural assay in mice, C391 dose-dependently (75g maximum effect) blocked the thermal hyperalgesia, mediated by mast cell degranulation. Conclusions and Implications C391 is the first low MW antagonist to block both PAR2 Ca2+ and MAPK signalling pathways activated by peptidomimetics and/or proteinase activation. C391 represents a new molecular structure for PAR2 antagonism and can serve as a basis for further development for this important therapeutic target.
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