Phospholipase C/DAG

Figure 1.10 Model of a G protein-coupled receptor with 7 membrane-spanning domains. Binding of an agonist to the receptor causes GDP to exchange with GTP. The a-GTP complex then dissociates from the receptor and the py complex and interacts with intercellular en mes or ion channels. The Py complex can activate an ion channel or possibly also interact with intercellular enzymes. GDP, guanine diphosphate GTP, guanine triphosphate cAMP, cyclic adenosine monophosphate PKC, protein kinase C PLC, phospholipase C DAG, diacylglycerol.

Fig. 2. Targeted lipidomics of 2-AG metabolism. Postulated pathways for 2-AG metabolism. Abbreviations PLC, phospholipase C DAG, diacylglycerol DGL, diacylglycerol lipase MGL, monoacylglycerol lipase PLA, phospholipase A AT, acyltransferase TAGL, triacylglycerol lipase PIP2, phosphatidylinositol bisphosphate ABHD-6/12 hydrolase lyso-PL, lysophospholipid lyso-PA, lysophosphatidic acid PA, phosphatidic add P, phosphatase COX, cydooxygen-ase LOX, lipoxygenase CYP450, cytochrome P450 CDP, cytidine diphosphate.

Fig. 10.1 The network of LPA and SIP signaling through Gprotein-coupled receptors. Each LPA and SI Preceptor couples to their specific class of Gproteins. Ligand binding activates or inhibits downstream second messenger molecules, and the most prominent cellular effects are illustrated. Rock, Rho-associated kinase SRF, serum response factor IPS, inositol 1,4,5-trisphosphate PLC, phospholipase C DAG, diacylglycerol PKC, protein kinase C MAPK, mitogen-activated protein kinase PI3K, phosphoinositol 3-kinase DAG, diacylglycerol...

Phospholipase C/DAG/IP3. The phosphoinositide system is an important intracellular messenger system. Two enzymes families are targets of G-proteins, phosphoinositide-specific phospholipase C (PLC), and phosphoinositide 3-kinase (PI3K). It is well established that receptor-dependent activation of phospholipase C (PLC) results in the... 

Figure 32.3 Inhibitory effects of iodide on human thyrocytes function, r, iodide NiS, sodium iodide symporter DUOX, duai oxidase TPO, thyroperoxidase TG, thyroglobulin TGI, iodinated thyroglobuiin X, the substrate converted into the active inhibitory iodinated molecule XI micro, micropinocytosis macro, macropinocytosis prolif, proliferation G.I., gene induction R, receptor Gs, stimulatory G protein of adenylyl cyclase AC, adenylyl cyclase cAMP, cyclic 3 -5 adenosine monophosphate PGE, prostaglandin E1 NE, norepinephrine Gq, stimulatory G protein of phospholipase C DAG, diacylglycerol IPS, inositol 1,4,5-trisphosphate Aa, amino acid ...

Figure 3. Pathways of phosphoinositide synthesis and interconversions. The figure shows the main pathways of phosphoinositide synthesis in mammalian cells. For the sake of clarity only the enzymatic activities (3-, 4- or 5-kinases or phosphatases) are indicated. In some cases the identification of key enzymes is mentioned (class I, II and III PI 3-kinases, PTEN, MTM, MTMR or SHIP). PI3K, phosphoinositide 3-kinase. PTEN, phosphatase and tensin homolog deleted on chromosome ten. MTM, myotubularin. MTMR, myotubular myopathy-related protein. SHIP, Src homology 2-containing inositol 5-phosphatase. PLC, phospholipase C. DAG, diacylglycerol.

FIGURE 2.7 Production of second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) through activation of the enzyme phospholipase C. This enzyme is activated by the a- subunit of Gq-protein and also by Py subunits of Gj-protein. IP3 stimulates the release of Ca2+ from intracellular stores while DAG is a potent activator of protein kinase C. 

Covalent regulation. Following occupation and activation of the M2 acetyl choline receptors, phospholipase C (PLC), is activated and both inositol (l,4,5)-trisphosphate (IP3), and diacylglycerol (DAG), are formed by hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2). 

Figure 10. The G-protein cascades in smooth muscle catalyze the exchange GDP for GTP on G-protein. Following the binding of GTP, the trimeric G-protein splits into an a-GTP part and a P-y part. The a-GTP part ordinarily then combines with its specific apoenzyme to constitute the active enzyme. For the activation of the contractile activation path, the enzyme is phospholipase C and the second messenger products are IP3 and DAG. The IP3 in the myoplasm binds to Ca channels in the SR membrane, opening them. Other second messengers include the inhibitors of contractile activity, cGMP and cAMP.

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. ...

A bacterial phosphatidylinositol specific phospholipase C (PI-PLC) had been available for many years before it was demonstrated to strip a number of membrane-bound proteins from eukaryotic cell surfaces [1], Such proteins are anchored by a PI moiety in which the 6 position of inositol is glycosidically linked to glucosamine, which in turn is bonded to a polymannan backbone (Fig. 3-10). The polysaccharide chain is joined to the carboxyl terminal of the anchored protein via amide linkage to ethanolamine phosphate. The presence of a free NH2 group in the glucosamine residue makes the structure labile to nitrous acid. Bacterial PI-PLC hydrolyzes the bond between DAG and phosphati-dylinositols, releasing the water-soluble protein polysac charide-inositol phosphate moiety. These proteins are tethered by glycosylphosphatidylinositol (GPI) anchors. 

The characteristics of the four major classes of histamine receptors are summarized. Question marks indicate suggestions from the literature that have not been confirmed. AA, arachidonic acid DAG, diacylglycerol Iko,2+, calcium-activated potassium current IP3, inositol 1,4,5-trisphosphate NHE, sodium-proton exchange, PKC, protein kinase C NO, nitric oxide PTPLC, phosphoinositide-specific phospholipase C TXA2, thromboxane A2. Has brain-penetrating characteristics after systemic administration. 

H linked intracellular messengers. Activated H receptors are known to activate a pertussis-toxin-insensitive G protein, Gq, that stimulates phosphoinositide-specific phospholipase C (PI-PLC), with the subsequent generation of inositol 1,4,5-trisphosphate (IP3) and diacylglyc-erol (DAG). These two mediators are known to elevate intracellular Ca2+ concentrations and to activate PKC,... 

This can be illustrated by known interactions between the cAMP and Ca2+ pathways. A first messenger that initially activates the cAMP pathway would be expected to exert secondary effects on the Ca2+ pathway at many levels via phosphorylation by PKA. First, Ca2+ channels and the inositol trisphosphate (IP3) receptor will be phosphorylated by PKA to modulate intracellular concentrations of Ca2+. Second, phospholipase C (PLC) is a substrate for PKA, and its phosphorylation modulates intracellular calcium concentrations, via the generation of IP3) as well as the activity of PKC, via the generation of DAG, and several types of CAMK. Similarly, the Ca2+ pathway exerts potent effects on the cAMP pathway, for example, by activating or inhibiting the various forms of adenylyl cyclase expressed in mammalian tissues (see Ch. 21). 

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