TY - JOUR T1 - The effects of an inhibitor of diglyceride lipase on collagen-induced platelet activation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.113.205591 SP - jpet.113.205591 AU - Elke C. J, Jackson AU - Giorgio Ortar AU - Archibald McNicol Y1 - 2013/01/01 UR - http://jpet.aspetjournals.org/content/early/2013/09/16/jpet.113.205591.abstract N2 - Human platelet activation by collagen occurs in a dose-dependent manner. High concentrations of collagen bind to a pair of receptors, the α2β1 integrin and GPVI/FcRγ, which stimulate a cascade of events including Syk, LAT, Btk , Gads and phospholipase Cγ2, leading to calcium release and protein kinase C (PKC) activation. Calcium and PKC are responsible for a range of platelet responses including exocytosis and aggregation, as well as the cytosolic phospholipase A2 (cPLA2)-mediated release of arachidonic acid which is converted to thromboxane (Tx) A2. In contrast low concentrations of collagen are acutely aspirin sensitive and, calcium release and aggregation are TxA2-dependent. Under these conditions cPLA2 is not involved and it has been suggested that phospholipase C generates diglyceride (DG) from which arachidonic acid is liberated by diacylglcerol lipase (DGL). Here a novel DGL blocker (OMDM-188), inhibited collagen-, but not arachidonic acid-, induced aggregation and TxA2 synthesis. Furthermore OMDM-188 inhibited collagen-induced arachidonic acid release. Finally OMDM-188 inhibited collagen-induced p38MAPK, but not ERK, phosphorylation, with no effect on the phosphorylation of either enzyme in response to arachidonic acid. Taken together these data suggest a role for a pathway involving PLC liberating DG from membrane phospholipids in response to minimally-activate concentrations of collagen. The DG serves as a substrate for DGL, potentially under the regulations of p38MAPK, to release arachidonic acid which is subsequently converted to TxA2 which mediates the final platelet response. ER -