Externalization of Phosphatidylserine

Kawai, K., Tyurina, Y.Y, Tyurin, V.A., Kagan, V.E., and Fabisiak, J., 2000, Peroxidation and externalization of phosphatidylserine in plasma membrane of HL-60 ceUs during tert-butyl hydroperoxide-induced apoptosis Role of cytochrome c, The Toxicologist 54 SuppL 776. 

It is now widely accepted that atherosclerosis is a chronic inflammatory arterial disease associated with risk factors, platelet, and other blood cells activities and their interactions with subendothelial cells, Activated platelets release active components from citosol and induce the externalization of phosphatidylserine through the flip-flop mechanism (23) that supports the function of the prothrombinase complex ending in thrombin generation,... 

Fabisiak, J.P., Kagan, V.E., Ritov, V.B., and Laso, J.S., 1997, Bcl-2 inhibits selective oxidation and externalization of phosphatidylserine during paraquat-induced apoptosis, Am. J. Physiol. (CellPhysiol.) 212 C675-C684. 

Balasubramanian, K., Miriukjoo, B., Schroit, A.J. (2007) Regulated externalization of phosphatidylserine at the cell surface implications for apoptosis. J. Biol. Chem. 282, 18357-18364. 

Yu, A., Byers, D. M., Ridgway, N. D., McMaster, C. R., and Cook, H. W., 2000, Preferential externalization of newly synthesized phosphatidylserine in apoptotic U937 ceUs is dependent on caspase-mediated pathways. Biochim. Biophys. Acta. 1487 296-308. 

Changes occur at the cell surface and plasma membrane in the early stages of apoptosis. One of the major plasma membrane alterations is the translocation of phosphatidylserine (PS) from the inner side of the plasma membrane to the outer layer for external exposure (FI). This change of exposure requires the activation of caspase-3, a Ca flux over the plasma membrane, and a change in Bcl-2 family (B8,B13, M6). 

The negatively charged phospholipid phosphatidylserine is asymmetrically distributed in mammalian cell membranes, primarily on the inner leaflet. Upon exposure to collagen or thrombin, the distribution of phospholipids changes with increasing phosphatidylserine in the external membrane leaf (I). The increased expression of phosphatidylserine on the outer leaflet of the membrane creates a procoagulant surface on which several steps of the coagulation cascade take place. 

Redistribution of phosphatidylserine (PS) to the surface of renal epithelial cells as a consequence of oxalate exposure was first seen by Wiessner et al. [30] and later confirmed by Cao et al. [31]. When cells were exposed to various levels of oxalate, a dose-dependent PS externalization occurred. PS is a phospolipid molecule normally present in the inner leaflet of the plasma membrane. Externalization of PS to the outer leaflet of the plasma membrane may play a role in induction of apoptosis and may serve as signal molecule to engulf these cells [32]. 

One of the early apoptotic events is exposure of phosphatidylserine normally present in the inner leaflet of the plasma membrane to the outer leaflet otherwise known as the phosphatidylserine flip (PS-flip) (27,28). Detection of the PS-flip is possible using annexin V, a 35 kDa protein with a high affinity for phosphatidylserine. Because of the nature of the PS-flip, annexin V is most useful in studying intact cells such as in flow cytometry or confo-cal microscopy. Cells in fixed tissue sections are not intact and use of labeled annexin V would not be able to differentiate between internal and external phosphatidylserine, though at least one investigator has attempted to circumvent this problem (29). 

PPD Purified protein derivative PPME Polymeric polysaccharide rich in mannose-6-phosphate moieties PRA Percentage reactive activity PRD, PRDII Positive regulatory domain, -II PR3 Proteinase-3 PRBC Parasitized red blood cell proET-1 Proendothelin-1 PRL Prolactin PRP Platelet-rich plasma PS Phosphatidylserine P-selectin Platelet selectin formerly known as platelet adctivation-dependent granule external membrane protein (PADGEM), granule membrane protein of MW 140 kD (GMP-140)... 

Platelet participation in normal hemostasis. The hemostatic plug is the specific response to external vessel lesion and depends on the extent of vessel wall damage, the specific interaction between endothelial cells and activated platelets, release of the contents of platelets intracellular granules in response to activation, the conjoint activity of activated factor Vll and platelet agonists, and the open conditions of blood flow. After activation, platelets also produce the external ization of membrane phosphatidylserine through the flip-flop mechanism that will support the function of the prothrombinase complex ending in thrombin generation and local clot formation. 

It is possible to monitor cardiac apoptosis in vivo in patients with acute MI. Hofstra et al. [124] used Tc-99m-labeled annexin V annexin V has a high affinity for phosphatidylserine which is known to be externalized from the inner mitochondrial membrane to the outer mitochondrial membrane during the process of apoptosis [125]. An increased uptake of annexin V in the infarcted region was demonstrated in patients with MI after reperfusion treatment. 

The membrane constituents are lipids (phospholipids, glycosphingolipids, and cholesterol Figure 10-5), carbohydrates, and proteins. The ratio of protein lipid carbohydrate on a weight basis varies considerably from membrane to membrane. For example, the human erythrocyte membrane has a ratio of about 49 43 8, whereas myelin has a ratio of 18 79 3. The composition of the normal human erythrocyte membrane is shown in Table 10-2. All membrane lipids are amphipathic (i.e., polar lipids). The polar heads of the phospholipids may be neutral, anionic, or dipolar. The surface of the membrane bears a net negative charge. The distribution of lipid constituents in the bilayer is asymmetrical. For example, in the erythrocyte membrane, phosphatidylethanolamine and phosphatidylserine are located primarily in the internal monolayer, whereas phosphatidylcholine and sphingomyelin are located in the external monolayer. 

Borisenko, G G, Matsura, T, Liu, S X, Tyurin, V A, Jianfei, J, Serinkan, F B, and Kagan, V E, Macrophage recognition of externalized phosphatidylserine and phagocytosis of apoptotic Jurkat cells-existence of a threshold. Arch. Biochem. Biophys. 413 (2003) 41-52. 

---