Phospholipase, Plasma

PH domains consist of about 120 amino acid residues. They do not interact with other proteins, but associate with specific polyphosphoinositides. Consequently, PH domains appear to be important for localizing target proteins to the plasma membrane. Examples of PH domain-containing proteins include phospholipase C andpl20/RasGAP (Fig. 1). 

The NHR contains also the conserved Calcineurin docking site, PxlxIT, required for the physical interaction of NEAT and Calcineurin. Dephosphorylation of at least 13 serines residues in the NHR induces a conformational change that exposes the nuclear localization sequences (NLS), allowing the nuclear translocation of NEAT. Rephosphorylation of these residues unmasks the nuclear export sequences that direct transport back to the cytoplasm. Engagement of receptors such as the antigen receptors in T and B cells is coupled to phospholipase C activation and subsequent production of inositol triphosphate. Increased levels of inositol triphosphate lead to the initial release of intracellular stores of calcium. This early increase of calcium induces opening of the plasma membrane calcium-released-activated-calcium (CRAC) channels,... 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and a-linolenate, or directly from dietary arachidonate and eicosapentaenoate (Figure 23-5). Arachidonate, usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase Aj (Figure 24-6)—but also from the diet—is the substrate for the synthesis of the PG2, 1X2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate (Figure 23-5). 

Immunologic abnormahties (eg, transfusion reactions, the presence in plasma of warm and cold antibodies that lyse red blood cells, and unusual sensitivity to complement) also fall in this class, as do toxins released by various infectious agents, such as certain bacteria (eg, Clostridium). Some snakes release venoms that act to lyse the red cell membrane (eg, via the action of phospholipases or proteinases). 

Ungemach, F.R. (1985). Plasma membrane damage of hepato-cytes following lipid peroxidation involvement of phospholipase A2. In Free Radicals in Liver Injury (eds. G. Poli, K.H. Cheeseman, M.U. Dianzani and T.F. Slater) pp. 127-134. IRL Press, Oxford. 

Tl. Takakuwa, T., Endo, S Nakae, H., Suzuki, T Inada, K., Yoshida, M Ogawa, M., and Uchi-da, K Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. Res. Commun. Chem. Pathol. Pharmacol. 84,271-281 (1994). 

LOX catalyzed the oxidation of arachidonoylphosphatidylcholine at both carbon-12 and carbon-15. Later on, it has been found [21] that reticulocyte lipoxygenase oxidized rat liver mitochondrial membranes, beef heart submitochondrial particles, rat liver endoplasmic membranes, and erythrocyte plasma membranes without preliminary release of unsaturated acids by phospholipases. 

Ca2+ can enter cells via voltage- or ligand-dependent channels and by capacitative entry. These three fundamental mechanisms of regulated calcium ion entry across the plasma membrane involve, respectively, voltage-dependent Ca2+ channels, ligand-gated Ca2+ channels and capacitative Ca2+ entry associated with phospholipase C-coupled receptors. 

Capacitative Ca2+ entry is the predominant mode of regulated Ca2+ entry in nonexcitable cells but it also occurs in a number of excitable cell types. This pathway of Ca2+ entry is usually associated with the activation of phospholipase C, which mediates the formation of IP3 (see Ch. 20). Intracellular application of IP3 mimics the ability of hormones and neurotransmitters to activate calcium ion entry, and activation of calcium ion entry by hormones and neurotransmitters can be blocked by intracellular application of low-molecular-weight heparin, which potently antagonizes IP3 binding to its receptor. There is considerable evidence for the presence of an IP3 receptor in the plasma membrane of some cells types. 1(1,3,4,5)P4, a product of IP3 phosphorylation, has been shown in some cells to augment this action of IP3 in activating PM calcium ion entry, but in others IP3 alone is clearly sufficient. 

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