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The Strathprints institutional repository is a digital archive of University of Strathclyde's Open Access research outputs. Strathprints provides access to thousands of Open Access research papers by University of Strathclyde researchers, including by researchers from the Department of Computer & Information Sciences involved in mathematically structured programming, similarity and metric search, computer security, software systems, combinatronics and digital health.

The Department also includes the iSchool Research Group, which performs leading research into socio-technical phenomena and topics such as information retrieval and information seeking behaviour.


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 1476-5381

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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.