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Pathway‐selective antagonism of proteinase activated receptor 2
Author(s) -
Suen J Y,
Cotterell A,
Lohman R J,
Lim J,
Han A,
Yau M K,
Liu L,
Cooper M A,
Vesey D A,
Fairlie D P
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12757
Subject(s) - rhoa , phosphorylation , microbiology and biotechnology , receptor , agonist , g protein coupled receptor , biology , signal transduction , protease activated receptor , protein kinase c , biochemistry , thrombin , immunology , platelet
Background and Purpose Proteinase activated receptor 2 ( PAR2 ) is a GPCR associated with inflammation, metabolism and disease. Clues to understanding how to block PAR2 signalling associated with disease without inhibiting PAR2 activation in normal physiology could be provided by studies of biased signalling. Experimental Approach PAR2 ligand GB 88 was profiled for PAR2 agonist and antagonist properties by several functional assays associated with intracellular G‐protein‐coupled signalling in vitro in three cell types and with PAR2 ‐induced rat paw oedema in vivo . Key Results In HT29 cells, GB 88 was a PAR2 antagonist in terms of Ca 2+ mobilization and PKC phosphorylation, but a PAR2 agonist in attenuating forskolin‐induced c AMP accumulation, increasing ERK1/2 phosphorylation, RhoA activation, myosin phosphatase phosphorylation and actin filament rearrangement. In CHO ‐h PAR2 cells, GB 88 inhibited Ca 2+ release, but activated G i/o and increased ERK1/2 phosphorylation. In human kidney tubule cells, GB88 inhibited cytokine secretion ( IL 6, IL 8, GM‐CSF , TNF ‐α) mediated by PAR2 . A rat paw oedema induced by PAR2 agonists was also inhibited by orally administered GB 88 and compared with effects of locally administered inhibitors of G ‐protein coupled pathways. Conclusions and Implications GB88 is a biased antagonist of PAR2 that selectively inhibits PAR2 / G q/11 / Ca 2+ / PKC signalling, leading to anti‐inflammatory activity in vivo , while being an agonist in activating three other PAR2 ‐activated pathways ( cAMP , ERK , R ho) in human cells. These findings highlight opportunities to design drugs to block specific PAR2 ‐linked signalling pathways in disease, without blocking beneficial PAR2 signalling in normal physiology, and to dissect PAR2 ‐associated mechanisms of disease in vivo .