Pathway-selective antagonism of proteinase activated receptor 2

Suen, J. Y., Cotterell, A., Lohman, R. J., Lim, J., Han, A., Yau, M. K., Liu, L., Cooper, M. A., Vesey, D. A. and Fairlie, D. P. (2014) Pathway-selective antagonism of proteinase activated receptor 2. British Journal of Pharmacology, 171 17: 4112-4124. doi:10.1111/bph.12757

Author 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.
Title Pathway-selective antagonism of proteinase activated receptor 2
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
Publication date 2014-09-01
Year available 2014
Sub-type Article (original research)
DOI 10.1111/bph.12757
Open Access Status Not Open Access
Volume 171
Issue 17
Start page 4112
End page 4124
Total pages 13
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Formatted abstract
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 GB88 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, GB88 was a PAR2 antagonist in terms of Ca2+ mobilization and PKC phosphorylation, but a PAR2 agonist in attenuating forskolin-induced cAMP accumulation, increasing ERK1/2 phosphorylation, RhoA activation, myosin phosphatase phosphorylation and actin filament rearrangement. In CHO-hPAR2 cells, GB88 inhibited Ca2+ release, but activated Gi/o and increased ERK1/2 phosphorylation. In human kidney tubule cells, GB88 inhibited cytokine secretion (IL6, IL8, GM-CSF, TNF-α) mediated by PAR2. A rat paw oedema induced by PAR2 agonists was also inhibited by orally administered GB88 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/Gq/11/Ca2+/PKC signalling, leading to anti-inflammatory activity in vivo, while being an agonist in activating three other PAR2-activated pathways (cAMP, ERK, Rho) 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.
Keyword Protease
Protease inhibitor
Proteinase activated receptor 2
Biased signalling
Cell signalling
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID APP1000745
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
Institute for Molecular Bioscience - Publications
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