Phospholipase inositol phospholipids

It has been indicated that the phosphodiesteratic cleavage of the Inositol phospholipids (phospholipase C activity) precedes and might trigger the activation of phospholipase A2 in stimulated platelets.1l >20,21 It seems that some of the products formed during the phosphodiesteratic cleavage of the inosltides could be related to Ca2+ mobilization. One of these products, myoinositol 1,4,5-trisphosphate. 

Eberhard, D. A., Cooper, C. L., Low, M. G. and Holz R. W. Evidence that the inositol phospholipids are necessary for exocytosis loss of inositol phospholipids and inhibition of secretion in permeabilized cells caused by a bacterial phospholipase C and removal of ATR Biochem. J. 268 15-25, 1990. 

Figure 14-3. Signaling through protein kinase C (PKC). Activated phospholipase C cleaves the inositol phospholipid PIP2 to form both soluble (IP3) and membrane-associated (DAG) second messengers. DAG recruits PKC to the membrane, where binding of calcium ions to PKC fully activates it. To accomplish this, IP3 promotes a transient increase of intracellular concentration by binding to a receptor on the endoplasmic reticulum, which opens a channel allowing release of stored calcium ions. PIP2, phosphatidylinositol 4,5-bisphosphate DAG, diacylglycerol PLC, phospholipase C IP3, inositol trisphosphate.

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). 

Rather than being reincorporated into inositol phospholipids, DAG can be broken down to release some arachidonate which is the precursor of prostaglandin E which, in turn, can react with plasma membrane receptors linked to adenyl cyclase and cAMP production. IL-3 does not activate phospholipase C but does promote phosphorylation of the glucose transporter by phosphokinase C (Dexter and Spooner, 1987). 

It was shown, however, that the ability of insulin to release GIPs could be mimicked by an inositol phospholipid-specific phospholipase C. This enzyme is distinct from the phospholipidase C which acts to break down polyphosphatidylinositols as it acts specifically on phosphatidylinositol and has been used to release proteins which are anchored to membranes by the covalent attachment to phosphatidylinositol... 

There is now considerable evidence to suggest that hormones which stimulate inositol phospholipid metabolism do so through a distinct G-protein [90-92]. It is thus possible that insulin might activate a G-protein in order to stimulate the proposed phosphatidylinositol-specific phospholipase C claimed to produce the GIPs insulin mediator (Fig. 4). 

Mueller-Roeber, B., and Pical, C., 2002, Inositol phospholipid metabolism in Arabidopsis. Characterized and putative isoforms of inositol phospholipid kinase and phosphoinositide-specific phospholipase C. Plant Physiol. 130 22—46. 

Rhee, S.G. (1991). Inositol phospholipid-specific phospholipase C interaction of yj isoform with tyrosine kinase. TIBS 16, 297 301. 

Phospholipase C acts on inositol phospholipids within the cell membrane to produce IP3, which opens up ion channels to facilitate entry of calcium into the cytoplasm where it acts as a messenger, and diacylglycerol, which modulates protorn kinase C activity. 

There are multiple phospholipase C s (PLCs) that are linked via G-proteins to neurotransmitter receptors. PLCs split the link between the Sn3 carbon and the phosphorus, thus generating two molecules the headgroup phosphate and diacylglycerol (DAG). PLCs particularly act on inositol phospholipids, generating inositol phosphates and DAG. As in the PLA2 cycle, both of these products are active signal transduction molecules. Again, the cycle must be terminated as shown in Fig. 2, by means of inositol phosphatases and DAG kinases. 

Rhee SG, Choi KD (1992) Regulation of inositol phospholipid-specific phospholipase C isozymes. J. Biol Chem., 267, 12393-12396. 

Figure 2.13. Histamine H,-receptor-mediated inositol phospholipid hydrolysis. Stimulation of H,-receptors leads to activation of a phospholipase C. probably via a guanine-nucleotide regulatory protein (N). which catalyses the hydrolysis of phosphatidylinositol 4.5 -bisphosphate (PIP2) to give inositol trisphosphate (IP3) and 1,2-diacylglycerol (DG). IP3 is then broken down by phosphatases to eventually yield free myo-inositol. Lithium ions can inhibit the conversion of inositol 1-phosphate (IP,) to myo-inositol. Free inositol then interacts with CDP-diacylglycerol,formed by a reaction between phosphatidic acid (PA) and CTP, to yield phosphatidylinositol (PI). Phosphorylation of PI by kinases completes the lipid cycle by reforming PIP2. Modified from [147,148].

Summary - In the last few years, it has become apparent that products derived from the action of phospholipases A2 and C are involved in the regulation of important cellular functions. Activation of phospholipase A2 catalyzes the liberation from phospholipids of eicosanoid precursors which lead to the formation of a wide range of physiologically active metabolites. Products derived from phospholipase C activity, which cleaves only the inositol phospholipids, are related to transmembrane signalling and can modulate reactions such as protein phosphorylation and the intracellular mobilization of Ca2+-ions. 

AG can be rapidly formed from inositol phospholipids (through combined actions of phospholipase C and diacylglycerol lipase or combined actions of phospholipase Aj and phospholipase C) or from other arachidonic-acid-containing phospholipids in a variety of tissues and cells upon stimulation (Sugiura et al., 1995 Stella et al., 1997 for reviews, Di Marzo, 1998 Piomelli et al., 1998, 2000 Di Marzo et al., 1999, 2002 ... 

Assays to Study Phospholipase D Regulation by Inositol Phospholipids and ADP-Ribosylation Factor 6... 

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