Picture of two heads

Open Access research that challenges the mind...

The Strathprints institutional repository is a digital archive of University of Strathclyde research outputs. Strathprints provides access to thousands of Open Access research papers by University of Strathclyde researchers, including those from the School of Psychological Sciences & Health - but also papers by researchers based within the Faculties of Science, Engineering, Humanities & Social Sciences, and from the Strathclyde Business School.

Discover more...

Dual effect of the novel peptide antagonist K-14585 on Proteinase-Activated Receptor-2 (PAR2)-mediated signalling

Goh, F.G. and Ng, P.Y. and Reilly, M. and Kanke, T. and Plevin, R. (2009) Dual effect of the novel peptide antagonist K-14585 on Proteinase-Activated Receptor-2 (PAR2)-mediated signalling. British Journal of Pharmacology, 158 (7). pp. 1695-1704. ISSN 0007-1188

Full text not available in this repository. (Request a copy from the Strathclyde author)


Here we have examined the effects of the novel peptide antagonist N-[1-(2,6-dichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indol-5-yl]aminocarbonyl}-glycinyl-L-lysinyl-L-phenylalanyl-N-benzhydrylamide (K-14585) on proteinase-activated receptor (PAR)2-mediated intracellular signalling events. Using NCTC2544 cells expressing PAR2, we assessed the effects of K-14585 on PAR2-mediated [3H] inositol phosphate accumulation, MAP kinase activation, p65 NFκB phosphorylation and DNA binding and IL-8 production. Pretreatment with K-14585 (5 µM) inhibited [3H] inositol phosphate levels stimulated by PAR2-activating peptide Ser-Leu-Ile-Gly-Lys-Val (SLIGKV-OH) in PAR2-expressing NCTC2544 cells. K-14585 pretreatment did not influence PAR2-mediated extracellular regulated kinase activation but inhibited p38 MAP kinase phosphorylation. At a higher concentration (30 µM), K-14585 alone stimulated p38 MAP kinase activation. These effects were replicated in EAhy926 cells, endogenously expressing PAR2, but not in parental or PAR4-expressing NCTC2544 cells, suggesting these effects were PAR2-dependent. SLIGKV-mediated stimulation of p38 MAP kinase phosphorylation was substantially reduced by the Gq/11 inhibitor YM-254890, without affecting K-14585-mediated phosphorylation. Pretreatment with K-14585 inhibited PAR2-mediated p65 NFκB phosphorylation and NFκB-DNA binding. K-14585 (30 µM) alone stimulated comparable NFκB reporter activity to SLIGKV-OH. K-14585 inhibited SLIGKV-stimulated IL-8 production, but given alone increased IL-8. While SLIGKV-induced IL-8 formation was reduced by both SB203580 and YM-254890, the response to K-14585 was sensitive to SB203580 but not YM-254890. These data reveal that K-14585 has a duality of action functioning both as an antagonist and agonist due to either partial agonist actions or possible agonist-directed signalling. The data also suggest two modes of p38 MAP kinase activation emanating from PAR2, one Gq/11-dependent and the other Gq/11-independent.