PT  - JOURNAL ARTICLE
AU  - Elke C. G. Jackson
AU  - Giorgio Ortar
AU  - Archie McNicol
TI  - The Effects of an Inhibitor of Diglyceride Lipase on Collagen-Induced Platelet Activation
AID  - 10.1124/jpet.113.205591
DP  - 2013 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 582--588
VI  - 347
IP  - 3
4099  - http://jpet.aspetjournals.org/content/347/3/582.short
4100  - http://jpet.aspetjournals.org/content/347/3/582.full
SO  - J Pharmacol Exp Ther2013 Dec 01; 347
AB  - 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 glycoprotein (GP)VI/Fc-receptor γ-chain (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 1,2-diacylglycerol (DG) from which arachidonic acid is liberated by diglyceride 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 phosphorylation, but not extracellular signal-regulated kinase (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 phospholipase C liberating DG from membrane phospholipids in response to minimally activating 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.