Diacylglycerol signal transduction

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

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. ...

Members of the protein kinase C family promote signal transduction by catalyzing ATP-dependent protein phosphorylation [general EC number 2.7.1.37] in response to various signals that promote lipid hydrolysis. The primary activator is diacylglycerol. See also Cal-cium/Calmodulin-Dependent Protein Kinase... 

Fig. 5.24 Classification of the phospholipases and the reaction of phospholipase C. a) Cleavage specificity of phospholipases Al, A2, C and D. b) Cleavage of inositol-containing phosphohpids by phospholipase C. In a reaction of particnlar importance for signal transduction, phosphohpase C (PL-C) catalyzes the cleavage of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2) into the messenger substances diacylglycerol and inositol 1,4,5-triphosphate (Ins(l,4,5)P3).

In addition to the membrane associated messenger substances diacylglycerol and PtdIns(3,4,5)P3 mentioned above, other hpoplulic compoimds have also been identified that are specifically formed in the process of signal transduction and which function as messenger substances (review Liscovitch and Cantely, 1994). Two such compounds are presented here ... 

Regulation by Ca and diacylglycerol identify protein kinase C as a component of signal transduction pathways, in the course of which, phospholipase C is activated and the messenger substances lns(3,4,5)P3/Ca and diacylglycerol are produced. Activation of protein kinase C may take place via two central pathways ... 

Phosphatidylinositol is synthesized by condensation of CDP-diacylglycerol with inositol (Fig. 21-26). Specific phosphatidylinositol kinases then convert phosphatidylinositol to its phosphorylated derivatives (see Fig. 10-17). Phosphatidylinositol and its phosphorylated products in the plasma membrane play a central role in signal transduction in eukaryotes (see Figs 12-8, 12-19). 

Figure 32.4. Cyclosporin A (CsA) disruption of signal transduction pathways leading to IL-2 production. CsA binds to cyclophilin in the cytoplasm. The complex disrupts at least two signaling pathways, decreasing activation of transcription factors AP-1 and NF-AT that lead to activation of genes involved in cytokine production. See text for detailed explanation. Abbreviations TCR, T-cell receptor PLC, phospholipase C IP3, inositol triphosphate PKC, protein kinase C DAG, diacylglycerol NF-AT, nuclear factor of activation PI, phophati-dylinositol PC, phosphatidylcholine.

Phospholipase C A family of intracellular enzymes central to many signal transduction pathways via effects on Ca + and protein kinase C. Phospholipase C catalyzes the hydrolysis of phosphoinositol 4,5-bisphosphate to yield 1,4,5-inositol triphosphate and diacylglycerol. See Irvine, R.F., The enzymology of stimulated inositol lipid turnover. Cell Calcium 3, 295-309,1982 Farese, R.V., Phospholipids as intermediates in hormone action. Mol. Cell Endocrinol. 35,1-14,1984 Majerus, P.W., The production... 

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