Diacylglycerols protein kinase activation

Diacylglycerol Protein kinase C activation Phospholipase C on P-inositol... 

Kunisaki, M., S.E. Bursell, F. Umeda, H. Nawata, and G.L. King. 1994. Normalization of diacylglycerol-protein kinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels. Diabetes 43 1372-1377. 

Diacylglycerol was mentioned as an activator of protein kinase C. In addition to diacylglycerol, protein kinase C is also activated by increased cellular calcium levels. Protein kinase C catalyzes, for example, the phosphorylation of G protein components the j8 subunit of the fiy complex and the a-GDP complex. Such phosphorylation apparently prevents the reassociation of the a-GDP with the fiy complex to give the G -GDP protein. It is thus clear that phosphorylation via protein kinase C participates in the regulation of G protein function. 

In addition to protein kinase C enzymes, cells contain other receptors for phorbol esters and diacylglycerol. In mammals, proteins named a- and /1-chimaerins have been identified that lack protein kinase activity and bind phorbol esters and diacylglycerol with high affinity. Therefore, not all biological responses elicited by phorbol ester treatment can be attributed to protein kinase C stimulation (review Ron and Kaza-nietz, 1999). 

Skin tumor promoters bring about a number of other important epigenetic changes in the skin such as membrane and differentiation alterations and an increase in protease activity, cAMP independent protein kinase activity and phospholipid synthesis (.31). In addition, the skin tumor promoters cause a decrease in epidermal superoxide dismutase and catalase activities as well as a decrease in the number of glucocorticoid receptors (.31). Some skin promoters appear to have a common mode of cellular action - via binding to the natural cellular substrate for diacylglycerol-a phospholipid, calcium-dependent kinase called protein kinase C. Promoters which interact with protein kinase C include 12-H-tetradecanoylphorbol-... 

We have already seen how the two products of phosphatidylinositol bisphosphate hydrolysis can interact through their cellular effects. A good example is liver, where the inositol 1,4,5-triphosphate/Ca pathway controls the activity of phosphorylase kinase whereas the diacylglycerol/ protein kinase C pathway switches off glycogen synthetase. 

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 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. 

Diacylglycerol is glycerol esterified to two fatty acids at the sn-1 and sn-2 positions. It is a membrane-embedded product of phospholipase C action and an activator of protein kinase C. It is also an intermediate in the biosynthesis of triacylglycerol, phosphatidyletha-nolamine and phosphatidylcholine. 

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. ...

Phorbol esters are promoters that interact with cellular receptors and activate protein kinase C. Usually protein kinase C is activated by Ca++ and diacylglycerol, both of which result from the hydrolysis of phosphoinositides catalyzed by phospholipase C. Phospholipase C is normally activated by several different growth factors. Thus phorbol esters bypass a tightly regulated step in the control of cell growth. Since protein kinase C phosphorylates various proteins, it is not known how this activity participates in establishing a cancerous line of cells. 

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. 

Protein kinase C is activated by the second messenger diacylglycerol 356... 

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