Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110)

Suen, J. Y., Barry, G. D., Lohman, R. J., Halili, M. A., Cotterell, A. J., Le, G. T. and Fairlie, D. P. (2012) Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). British Journal of Pharmacology, 165 5: 1413-1423. doi:10.1111/j.1476-5381.2011.01610.x

Author Suen, J. Y.
Barry, G. D.
Lohman, R. J.
Halili, M. A.
Cotterell, A. J.
Le, G. T.
Fairlie, D. P.
Title Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110)
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
Publication date 2012-03-01
Year available 2011
Sub-type Article (original research)
DOI 10.1111/j.1476-5381.2011.01610.x
Open Access Status Not Open Access
Volume 165
Issue 5
Start page 1413
End page 1423
Total pages 11
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Formatted abstract
Background and Purpose. Many cells express Proteinase Activated Receptor 2 (PAR2) on their plasma membrane. PAR2 is a sensor for proteolytic enzymes (e.g. trypsin, tryptase) which prune the receptor N-terminus, enabling it to signal via its transmembrane domain to intracellular G proteins that activate signaling networks. Studies on PAR2 in physiology and disease have relied heavily upon activating effects of proteases and peptide agonists that lack stability and bioavailability in vivo.
Experimental Approach. Novel small molecule agonist GB110 and antagonist GB88 were characterized in vitro using trypsin, peptide agonists, PAR2 antibody, PAR1 agonists and flow cytometry; compared in 7 cell lines using intracellular calcium mobilization; and examined in vivo against PAR2- vs PAR1- induced rat paw odema.
Results. GB110 is a potent non-peptidic agonist that activates PAR2-mediated Ca2+ release in HT29 cells (EC50∼200 nM) and 6 other human cell lines, inducing PAR2 internalization. GB88 is a unique PAR2 antagonist, inhibiting PAR2 activated Ca2+ release (IC50∼2 µM) induced by native (e.g. trypsin) or synthetic (e.g. peptide, nonpeptide) agonists. GB88 is a competitive and surmountable antagonist of agonist 2f-LIGRLO-NH2, a competitive but insurmountable antagonist of agonist GB110, and a noncompetitive insurmountable antagonist of trypsin. Antagonist GB88 is orally active and anti-inflammatory in vivo, inhibiting acute rat paw oedema elicited by agonist GB110 and proteolytic or peptide agonists of PAR2 but not by corresponding agonists of PAR1 or PAR4.
Conclusions. The novel PAR2 agonist and antagonist modulate intracellular Ca2+ and rat paw oedema, providing novel molecular tools for interrogating PAR2-mediated diseases.
Keyword Proteinase activated receptor 2
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes © 2011 The Authors. British Journal of Pharmacology. © 2011 The British Pharmacological Society.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
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Created: Mon, 31 Oct 2011, 23:01:26 EST by Dr Jacky Suen on behalf of Institute for Molecular Bioscience