PT - JOURNAL ARTICLE AU - Virginie Aires AU - Aziz Hichami AU - Rodolphe Filomenko AU - Aude Plé AU - Cédric Rébé AU - Ali Bettaieb AU - Naim Akhtar Khan TI - Docosahexaenoic Acid Induces Increases in [Ca<sup>2+</sup>]<sub>i</sub> via Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells AID - 10.1124/mol.107.039792 DP - 2007 Dec 01 TA - Molecular Pharmacology PG - 1545--1556 VI - 72 IP - 6 4099 - http://molpharm.aspetjournals.org/content/72/6/1545.short 4100 - http://molpharm.aspetjournals.org/content/72/6/1545.full SO - Mol Pharmacol2007 Dec 01; 72 AB - We investigated, in monocytic leukemia U937 cells, the effects of docosahexaenoic acid (DHA; 22:6 n-3) on calcium signaling and determined the implication of phospholipase C (PLC) and protein kinase C (PKC) in this pathway. DHA induced dose-dependent increases in [Ca2+]i, which were contributed by intracellular pool, via the production of inositol-1,4,5-triphosphate (IP3) and store-operated Ca2+ (SOC) influx, via opening of Ca2+ release-activated Ca2+ (CRAC) channels. Chemical inhibition of PLC, PKCγ, and PKCδ, but not of PKCβ I/II, PKCα, or PKCβI, significantly diminished DHA-induced increases in [Ca2+]i. In vitro PKC assays revealed that DHA induced a ∼2-fold increase in PKCγ and -δ activities, which were temporally correlated with the DHA-induced increases in [Ca2+]i. In cell-free assays, DHA, but not other structural analogs of fatty acids, activated these PKC isoforms. Competition experiments revealed that DHA-induced activation of both the PKCs was dose-dependently inhibited by phosphatidylserine (PS). Furthermore, DHA induced apoptosis via reactive oxygen species (ROS) production, followed by caspase-3 activation. Chemical inhibition of PKCγ/δ and of SOC/CRAC channels significantly attenuated both DHA-stimulated ROS production and caspase-3 activity. Our study suggests that DHA-induced activation of PLC/IP3 pathway and activation of PKCγ/δ, via its action on PS binding site, may be involved in apoptosis in U937 cells. The American Society for Pharmacology and Experimental Therapeutics