The linoleic acid derivative DCP-LA selectively activates PKC-ε, possibly binding to the phosphatidylserine binding site

This study examined the effect of 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis-double bonds, on protein kinase C (PKC) activity. In the in situ PKC assay with reverse-phase high-performance liquid chromatography, DCP-LA significantly activated PKC in PC-12 cells in a concentration-dependent (10 nM–100 µM) manner, with the maximal effect at 100 nM, and the DCP-LA effect was blocked by GF109203X, a PKC inhibitor, or a selective inhibitor peptide of the novel PKC isozyme PKC-ε. Furthermore, DCP-LA activated PKC in HEK-293 cells that was inhibited by the small, interfering RNA against PKC-ε. In the cell-free PKC assay, of the nine isozymes examined here, DCP-LA most strongly activated PKC-ε, with >7-fold potency over other PKC isozymes, in the absence of dioleoyl-phosphatidylserine and 1,2-dioleoyl-sn-glycerol; instead, the DCP-LA action was inhibited by dioleoyl-phosphatidylserine. DCP-LA also activated PKC-γ, a conventional PKC, but to a much lesser extent compared with that for PKC-ε, by a mechanism distinct from PKC-ε activation. Thus, DCP-LA serves as a selective activator of PKC-ε, possibly by binding to the phosphatidylserine binding site on PKC-ε. These results may provide fresh insight into lipid signaling in PKC activation.