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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Effect of the non-peptide blocker (+/-) CP 96,345 on the cellular mechanism involved in the response to NK1 receptor stimulation in human skin fibroblasts.

The effect of the selective non-peptide antagonist for NK1 receptors (+/-)CP 96,345 on cellular transduction mechanisms elicited by the NK1 selective agonist [Sar9]-substance P-sulfone ([Sar9]-SP) was investigated in a stabilized culture of human skin fibroblasts (HF) and compared to the effects of two peptide antagonists, FK 888 and GR 82, 334. The exposure of the cells to [Sar9]-SP (100 nM) produced an early increase in inositol 1,4,5-trisphosphate (IP3) level, which peaked after 6 s, and a later rise in cellular inositol 1-phosphate (IP1) content which reached the maximum level in 15 min. The cAMP level was not significantly modified. The increase in IP1 was greatly reduced, at approximately the same extent by the 10 min pretreatment with a concentration of (+/-)CP 96,345 (100 nM) 10 times smaller than that of FK 888 and GR 82,334 (1 microM). The cytosolic Ca2+ mobilization in response to the NK1 agonist was monitored both by spectrofluorimetric and single-cell image analysis determinations on adherent cells loaded with the Ca(2+)-sensitive fluorescent indicators Fura-2/AM and Indo-1, respectively. [Sar9]-SP (100 nM) produced a rapid increase in the intracellular Ca2+ level in Fura-2/AM loaded cells. Cytosolic Ca2+ mobilization, measured by single-cell image analysis, indicated a concentration-dependent increase in both the ratio and in the number of cells responding to [Sar9]-SP. Either the non-peptide or the peptide selective NK1 receptor antagonists inhibited the increase in Ca2+ level in both the assays. In the spectrofluorimetric experiments the antagonizing effects of (+/-)CP 96,345 (1-100 nM), FK 888 (10 nM-1 microM) and GR 82,334 (10 nM-1 microM) were concentration-dependent. Moreover, the non-peptide antagonist was more potent than the two peptide antagonists, producing an 82.5% inhibition of Ca2+ mobilization at a concentration (10 nM) at which FK 888 and GR 82,334 decreased the response by only 62.3 and 60%, respectively. Stimulation of phosphatidylinositol turnover and calcium mobilization were also induced by 10 nM bradykinin; these effects were influenced neither by the previous administration of the NK1 receptor agonist nor by the three antagonists tested. These results demonstrate that the cellular transduction mechanisms induced in human skin fibroblasts by NK1 receptor stimulation are specifically and effectively antagonized by (+/-)CP 96,345, and that this non-peptide antagonist is more potent than the two peptide antagonists tested.[1]


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