RT Journal Article
SR Electronic
T1 Docosahexaenoic Acid Induces Increases in [Ca2+]i via Inositol 1,4,5-Triphosphate Production and Activates Protein Kinase Cγ and -δ via Phosphatidylserine Binding Site: Implication in Apoptosis in U937 Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1545
OP 1556
DO 10.1124/mol.107.039792
VO 72
IS 6
A1 Virginie Aires
A1 Aziz Hichami
A1 Rodolphe Filomenko
A1 Aude Plé
A1 Cédric Rébé
A1 Ali Bettaieb
A1 Naim Akhtar Khan
YR 2007
UL http://molpharm.aspetjournals.org/content/72/6/1545.abstract
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