科研之友
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摘要
Human platelet activation by collagen occurs in a dose-dependent manner. High concentrations of collagen bind to a pair of receptors, the alpha 2 beta 1 integrin and glycoprotein (GP)VI/Fc-receptor gamma-chain (FcR gamma), which stimulate a cascade of events including Syk, LAT, Btk, Gads, and phospholipase C gamma 2, 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 A(2) (cPLA(2))-mediated release of arachidonic acid, which is converted to thromboxane (Tx)A(2). In contrast, low concentrations of collagen are acutely aspirin-sensitive, and calcium release and aggregation are TxA(2)-dependent. Under these conditions, cPLA(2) 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 TxA(2) synthesis. Furthermore, OMDM-188 inhibited collagen-induced arachidonic acid release. Finally OMDM-188 inhibited collagen-induced p38(MAPK) 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 TxA(2), which mediates the final platelet response.
- 出版日期2013-12
