| Autor: |
Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ, Le GT, Fairlie DP, Suen, J Y, Barry, G D, Lohman, R J, Halili, M A, Cotterell, A J, Le, G T, Fairlie, D P |
| Zdroj: |
British Journal of Pharmacology; Mar2012, Vol. 165 Issue 5, p1413-1423, 11p |
| Abstrakt: |
Background and Purpose: Many cells express proteinase activated receptor 2 (PAR2) on their plasma membrane. PAR2 is activated by proteolytic enzymes, such as trypsin and tryptase that cleave the receptor N-terminus, inititating signalling to intracellular G proteins. Studies on PAR2 have relied heavily upon activating effects of proteases and peptide agonists that lack stability and bioavailability in vivo.Experimental Approach: A novel small molecule agonist GB110 and an antagonist GB88 were characterized in vitro against trypsin, peptide agonists, PAR2 antibody, PAR1 agonists and flow cytometry,in seven cell lines using intracellular Ca(2+) mobilization and examined in vivo against PAR2- and PAR1-induced rat paw oedema.Key Results: GB110 is a potent non-peptidic agonist activating PAR2-mediated Ca(2+) release in HT29 cells (EC(50) ∼200 nM) and six other human cell lines, inducing PAR2 internalization. GB88 is a unique PAR2 antagonist, inhibiting PAR2 activated Ca(2+) release (IC(50) ∼2 µM) induced by native (trypsin) or synthetic peptide and non-peptide agonists. GB88 was a competitive and surmountable antagonist of agonist 2f-LIGRLO-NH(2), a competitive but insurmountable antagonist of agonist GB110, and a non-competitive insurmountable antagonist of trypsin. GB88 was 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 and Implications: The novel PAR2 agonist and antagonist modulate intracellular Ca(2+) and rat paw oedema, providing novel molecular tools for examining PAR2-mediated diseases. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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