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Journal of Lipid Research, Vol. 47, 1146-1156, June 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Takeshi Kanno^*, Hideyuki Yamamoto^*, Takahiro Yaguchi^*, Rika Hi^*, Takeshi Mukasa^*, Hirokazu Fujikawa^*, Tetsu Nagata^*, Satoshi Yamamoto^*, Akito Tanaka and Tomoyuki Nishizaki^1,*

^* Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan
Chemistry Department, Reverse Proteomics Research Institute Co. Ltd., Kisarazu, Chiba 292-0818, Japan

Published, JLR Papers in Press, March 6, 2006.

¹ To whom correspondence should be addressed. e-mail: tomoyuki{at}hyo-med.ac.jp

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-. Furthermore, DCP-LA activated PKC in HEK-293 cells that was inhibited by the small, interfering RNA against PKC-. In the cell-free PKC assay, of the nine isozymes examined here, DCP-LA most strongly activated PKC-, 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-, a conventional PKC, but to a much lesser extent compared with that for PKC-, by a mechanism distinct from PKC- activation. Thus, DCP-LA serves as a selective activator of PKC-, possibly by binding to the phosphatidylserine binding site on PKC-. These results may provide fresh insight into lipid signaling in PKC activation.

Supplementary key words 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid • protein kinase C- • protein kinase C-

Abbreviations: ACh, acetylcholine; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; DCP-LA, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid; dNTP, deoxynucleoside triphosphate; MALDI-TOF MS, matrix-assisted laser desorption ionization time-of-flight mass spectrometry; MW, molecular weight; PKA, protein kinase A; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; siRNA, small interfering RNA

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