Platelet activation phospholipases

CoUagen-induced activation of a platelet phospholipase A2 by increased levels of cytosolic Ca results in hberation of arachidonic acid from platelet phospho-hpids, leading to the formation of thromboxane A2 (Chapter 23), which in turn, in a receptor-mediated fashion, can further activate phospholipase C, promot-ing platelet aggregation. 

The mechanisms involved in platelet activation are discussed in Chapter 51 (see Figure 51-8). The process involves interaction of the stimulus (eg, thrombin) with a receptor, activation of G proteins, stimulation of phospholipase C, and hberation from phosphatidylinositol... 

Hendrickson, H. S., Hendrickson, E. K., Johnson, I. D. and Farber, S. A. (1999). Intramolecularly quenched BODIPY-labeled phospholipid analogs in phospholipase A(2) and platelet-activating factor acetylhydrolase assays and in vivo fluorescence imaging. Anal. Biochem. 276, 27-35. 

Esterases play a role in regulating the platelet-activating factor (PAF), a lipid with hypotensive properties [96], Phospholipase A2 (EC 3.1.1.4) is involved in this pathway by hydrolyzing a precursor to lyso-PAF and a free fatty acid. The activity of PAF, formed by acetylation of lyso-PAF, is controlled by an esterase hydrolyzing the acetate moiety [100]. 

L. W. Tjoelker, C. Eberhardt, J. Unger, H. Letrong, G. A. Zimmerman, T. M. McIntyre, D. M. Stafforini, S. M. Prescott, P. W. Gray, Plasma Platelet-Activating Factor Acetyl-hydrolase Is a Secreted Phospholipase A2 with a Catalytic Triad ,./. Biol. Chem. 1995, 270, 25481-25487. 

Since predators of snakes (and humans) have to deal with snake venoms as defenses, they are included here, even though they serve in predation. Snake venoms are primarily enzymes (proteins), especially of the phospholipase A2 type, which breaks down cell membrane phospholipids hydrolytically. Other snake venoms such as cobrotoxin contain peptides with 60-70 amino acid residues. Pharmacologically, they have neurotoxic, cytotoxic, anticoagulant, and other effects. The neurotoxins, in turn, can have pre- or postsynaptic effects. Snake venoms with both neurotoxic and hemolytic effects on the heart are known as cardiotoxins. Cytotoxins attach to the cells of blood vessels and cause hemorrhage. Snake venom factors may stimulate or inhibit blood clotting. Finally, platelet-active factors can contribute to hemorrhage. 

Platelet activation occurs in large part via G protein-coupled agonist receptors and intracellular signaling events that involve activation of phospholipase C (PLC). PLC catalyzes the breakdown of plasma membrane inositol phospholipids, resulting in generation of 1,2-diacylglycerol (DAG) and 1,4,5-inositol triphosphate (IP3). DAG activates protein kinase C, and IP3 induces mobilization of calcium from intracellular stores (10). 

In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by reducing the prostaglandin, leukotriene, and platelet-activating factor synthesis that results from activation of phospholipase - Finally, glucocorticoids reduce expression... 

FI Naraba, Y Imai, I Kudo, Y Nakagawa, S Oh-ishi. Activation of phospholipase A2 and acylation of lysophospholipids the major regulators for platelet activating factor production in rat neutrophils. J Biochem (Tokyo) 118 442-447, 1995. 

The homology of p36 with lipocortin II and its ability to inhibit pancreatic phospholipase A2 suggests a possible but unproven role as inhibitor of intracellular phospholipase A2 [86]. Phospholipase A2 activity provides one of the many means of arachidonate production which would have important consequences to the activation of secretory response and membrane fusion events. The observation that the 40 kDa protein kinase C substrate, whose phosphorylation state changes dramatically upon platelet activation, may partially cross-react with a polyclonal antibody raised to rat renal lipocortin, is therefore interesting [120]. An alternate sug-... 

Hakkinen, T, Luoma, JS, Hiltunen, MO, Macphee, CH, Milliner, KJ, Patel, L, Rice, SQ, Tew, DG, Karkola, K, and Yla-Herttuala, 1999, Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions, Arterioscler. Thromb. Vase. Biol. 19 2909-2917. 

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