Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphatidic acid is formed by platelets as a result of the combined activities of phospholipase C and diacylglycerol kinase. The initial thrombin-activated phospholipase C-mediated reaction is quinacrine insensitive and is followed by quinacrine-sensitive phospholipase A2 activities. The phosphatidic acid released probably results in cellular calcium gating, which, among other actions, might release arachidonic acid by activating phospholipases A2. Indeed, we have detected a phosphatidic acid-specific phospholipase A2 in platelets, which might have an important role in the liberation of arachidonic acid.
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PMID:The importance of the production of phosphatidic acid for the release of arachidonic acid in stimulated platelets. 680 30

The effects of polyvalent cations (polyamines and aminoglycoside antibiotics) on Ca2+-dependent phosphatidylinositol-specific phospholipase C activity of human amnion tissue were examined. In the presence of 1 mM Ca2+, the hydrolysis of phosphatidylinositol (2 mM) by phospholipase C was increased greatly (240-560% of control) by spermine (0.4 mM), spermidine (1 mM), neomycin (0.1 mM), gentamicin (0.2 mM), kanamycin (0.4 mM) and streptomycin (0.8 mM). Putrescine and cadaverine (0.1-2.0 mM), however, stimulated phospholipase C activity only slightly. The effects of spermidine, spermine and gentamicin on phospholipase C activity were characterized and found to be dependent upon the concentrations of phosphatidylinositol, Ca2+ and the particular polyvalent cation. At low concentrations of phosphatidylinositol and Ca2+ the predominant effect of polyamines and aminoglycosides was to inhibit phospholipase C activity. When the concentrations of phosphatidylinositol and Ca2+ were increased, spermidine, spermine and gentamicin stimulated phospholipase C activity. In the presence of 16 mM Ca2+, however, phospholipase C activity was maximal and was unaffected by either polyamines or aminoglycosides. At all concentrations of Ca2+ examined, the maximal stimulation of phospholipase C activity by a given polyvalent cation occurred at a fixed molar ratio of the particular polyvalent cation to phosphatidylinositol. Polyamines and aminoglycosides appeared to modulate the Ca2+ requirement for phospholipase C activity, but could not substitute completely for Ca2+. The activities of phospholipase A2, diacylglycerol lipase, monoacylglycerol lipase and diacylglycerol kinase in amnion tissue were unaffected by any of the polyvalent cations examined. It is proposed that any in vivo influences (stimulatory or inhibitory) of polyamines and aminoglycosides on amnion phospholipase C activity would depend upon the effective concentrations of Ca2+ and phosphatidylinositol.
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PMID:The effects of polyamines and aminoglycosides on phosphatidylinositol-specific phospholipase C from human amnion. 684 63

The time course experiments of 32Pi-labelling and breakdown of phospholipids in rabbit leukocytes exposed to leukocidin from Pseudomonas aeruginosa suggested that the initial action of this toxin was to stimulate phosphatidic acid production, presumably by causing a rapid metabolic change of phosphatidylinositol (PI response) correlating with phosphatidylinositol-specific phospholipase C and 1,2-diacylglycerol kinase. It appears that a rapid formation of phosphatidic acid and degradation of polyphosphoinositides in leukocytes treated with the toxin might be related a Ca2+-movement from extra- and intracellular spaces, resulting in the activation of Ca2+-dependent enzymes involved in the leukocidic process.
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PMID:A rapid stimulation of phosphatidylinositol metabolism in rabbit leukocytes by pseudomonal leukocidin. 686 19

Endogenous phospholipid metabolism in stimulated human platelets was studied by phosphorus assay of major and minor components following separation by two-dimensional thin-layer chromatography. This procedure obviated the use of radioactive labels. Extensive changes were found in quantities of phosphatidylinositol (PI) and phosphatidic acid (PA) as a consequence of thrombin or collagen stimulation. Thrombin addition was followed by rapid alterations in the amount of endogenous PI and PA. The decrease in PI was not precisely reciprocated by an increase in PA when thrombin was the stimulus. This apparent discrepancy could be explained by removal of a transient intermediate in PI metabolism, such as diglyceride, formed by PI-specific phospholipase C (Rittenhouse-Simmons, S., J. Clin. Invest.63: 580-587, 1979). Diglyceride would be unavailable for PA formation by diglyceride kinase, if hydrolyzed by diglyceride lipase (Bell, R. L., D. A. Kennerly, N. Stanford, and P. W. Majerus. Proc. Natl. Acad. Sci. U. S. A.76: 3238-3241, 1979) to yield arachidonate for prostaglandin endoperoxide formation. Thrombin-treated platelets also accumulated lysophospho-glycerides. Specifically, lysophosphatidyl ethanolamines accumulated within 15s following thrombin addition. Fatty acid and aldehyde analysis indicated phospholipase A(2) activity, with an apparent preference for diacyl ethanolamine phosphoglycerides. In the case of collagen, these changes occurred concomitantly with aggregation and consumption of oxygen for prostaglandin endoperoxide formation.THESE STUDIES OF ENDOGENOUS PHOSPHOLIPID METABOLISM PROVIDE INFORMATION SUPPORTING THE EXISTENCE OF TWO PREVIOUSLY POSTULATED PATHWAYS FOR LIBERATION OF ARACHIDONIC ACID FROM PLATELET PHOSPHOLIPIDS: (a) the combined action of PI-specific phospholipase C plus diglyceride lipase yielding arachidonate derived from PI; and (b) a phospholipase A(2) acting primarily on diacyl ethanolamine phosphoglyceride.
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PMID:Phospholipid metabolism in stimulated human platelets. Changes in phosphatidylinositol, phosphatidic acid, and lysophospholipids. 740 Mar 15

The regulation of phosphatidylcholine (PtdCho) hydrolysis by Ca2+ and protein kinase C (PKC) was measured in [3H]palmitate-labelled cultured guinea-pig airway smooth-muscle cells as phosphatidylbutanol ([3H]PtdBut) and phosphatidate ([3H]PtdOH) formation in the presence of butanol. The former is a direct measure of phospholipase D (PLD) activity, whereas the latter, in airway smooth muscle, is indicative of net PtdCho-specific phospholipase C (PLC)-like/diacylglycerol (DG) kinase activity. Bradykinin-stimulated responses exhibited a requirement for extracellular Ca2+ influx, since they were inhibited in the presence of EGTA. This influx was independent of voltage-operated channels, since the L-type channel blocker nifedipine (up to 10 microM) was without effect on bradykinin-stimulated responses. In support of this, membrane depolarization with KCl (30 mM) failed to elicit either response. However, bradykinin-stimulated formation of both [3H]PtdBut and [3H]PtdOH was partially inhibited by 100 microM SKF96365. Ionomycin, a Ca2+ ionophore, induced PtdCho hydrolysis to a greater extent than bradykinin, also in an extracellular-Ca(2+)-dependent manner. Thapsigargin-induced emptying of intracellular Ca2+ pools elicited the formation of both [3H]PtdBut and [3H]PtdOH and displayed a requirement for extracellular Ca2+. Bradykinin-stimulated PtdCho-specific PLC-like/DG kinase pathway and PLD responses were unaffected by thapsigargin pretreatment, thereby questioning the role of Ins(1,4,5)P3/Ins(1,3,4,5)P4-dependent Ca2+ stores in the receptor stimulation of these activities in airway smooth-muscle cells. In this regard, we have previously demonstrated that the bradykinin-stimulated PtdCho-specific PLD and PLC-like activities can occur under conditions of apparent complete blockade of bradykinin-stimulated Ins(1,4,5)P3 formation by receptor antagonist in guinea-pig airway smooth muscle. The PKC inhibitor, Ro31-8220, selectively blocked both bradykinin- and ionomycin-stimulated PLD activity in a concentration-dependent manner (IC50 approx. 1 microM), but was without effect on bradykinin-stimulated PtdCho-PLC-like/DG kinase-derived PtdOH formation. In contrast, an inhibitor of PtdCho-PLC, D609, selectively blocked the formation of [3H]PtdOH in the presence of butanol (PtdCho-PLC-like/DG kinase activity), but not [3H]PtdBut formation. In conclusion, PtdCho hydrolysis appears to occur via two distinguishable routes which both require extracellular Ca2+, whereas only the PLD route is regulated by PKC.
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PMID:Bradykinin-stimulated phosphatidylcholine hydrolysis in airway smooth muscle: the role of Ca2+ and protein kinase C. 748 7

The effects of cochlioquinone A, isolated from Drechslera sacchari, were studied in vitro and in vivo. This compound specifically inhibited diacylglycerol kinase activity with Ki = 3.1 microM. The kinetics revealed that cochlioquinone A inhibited diacylglycerol kinase in competition with ATP, and non-competitively with diacylglycerol. The compound inhibited neither protein kinase C, epidermal growth factor receptor-associated protein tyrosine kinase, nor phospholipase C. Cochlioquinone A reduced the concentration of phosphatidic acid in T cell lymphoma with a half maximal concentration of 3 microM, and simultaneously augmented the phosphorylation of 80 kDa protein, a known substrate of protein kinase C. The degree of the phosphorylation of 80 kDa protein in the presence of cochlioquinone A was similar to that in the presence of phorbol myristate acetate (0.1 microgram/ml). These results demonstrate that cochlioquinone A is a specific inhibitor of diacylglycerol kinase, which regulates the activity of protein kinase C.
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PMID:Cochlioquinone A, an inhibitor of diacylglycerol kinase. 749 Feb 10

Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and endotoxin (LPS) are potent pro-inflammatory mediators which induce multiple and diverse biological responses in a wide variety of cell types. However, these pro-inflammatory mediators also have significant overlap and redundancy in their biological effects. This suggests that there is significant diversity in second messenger signal transduction systems induced by these stimuli to explain the diversity in biological responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli may be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocytic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species vary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl ether), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger activities, many of the PA species induced are converted to diacylglycerol species (DG), which are structurally distinct from the DGs generated by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta or LPS. TNF alpha-induced sphingomyelin hydrolysis, PLC-mediated PC hydrolysis, and DG kinase-mediated PA formation or TNF alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute inflammatory animal models that may be due to inhibition of this shared second messenger pathway involving PA.
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PMID:Potential role for phosphatidic acid in mediating the inflammatory responses to TNF alpha and IL-1 beta. 770 34

Glycoprotein IIb/IIIa has been proposed as the platelet receptor for high density lipoproteins (HDL3). We characterized the HDL3-induced second messenger response in normal and glycoprotein IIb/IIIa-deficient platelets. In normal platelets physiological concentrations of HDL3 induced the time-dependent generation of phosphatidic acid in the absence of phosphoinositide turnover. The rise in phosphatidic acid preceded that of diacyglycerol which was inconsistent with phospholipase C/diacylglycerol kinase pathway being the source of phosphatidic acid and suggested the involvement of phospholipase D. In the presence of butanol, HDL3 stimulated the accumulation of phosphatidylbutanol, an unequivocal indicator of phospholipase D activity. No increase in phosphatidic acid, diacylglycerol, and phosphatidylbutanol was observed upon addition of HDL3 to glycoprotein IIb/IIIa-deficient platelets. We conclude that phosphatidic acid is generated in HDL3-stimulated platelets by phospholipase D and that glycoprotein IIb/IIIa is the receptor involved in this process.
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PMID:HDL3 activates phospholipase D in normal but not in glycoprotein IIb/IIIa-deficient platelets. 785 58

Phosphatidic acid has been proposed to contribute to the mitogenic actions of various growth factors. In 32P-labeled neonatal rat cardiac fibroblasts, 100 nM [Sar1]angiotensin II was shown to rapidly induce formation of 32P-phosphatidic acid. Levels peaked at 5 min (1.5-fold above control), but were partially sustained over 2 h. Phospholipase D contributed in part to phosphatidic acid formation, as 32P- or 3H-phosphatidylethanol was produced when cells labeled with [32P]H3PO4 or 1-O-[1,2- 3H]hexadecyl-2-lyso-sn-glycero-3-phosphocholine were stimulated in the presence of 1% ethanol. [Sar1]angiotensin II-induced phospholipase D activity was transient and mainly mediated through protein kinase C (PKC), since PKC downregulation reduced phosphatidylethanol formation by 68%. Residual activity may have been due to increased intracellular Ca2+, as ionomycin also activated phospholipase D in PKC-depleted cells. Phospholipase D did not fully account for [Sar1]angiotensin II-induced phosphatidic acid: 1) compared to PMA, a potent activator of phospholipase D, [Sar1]angiotensin II produced more phosphatidic acid relative to phosphatidylethanol, and 2) PKC downregulation did not affect [Sar1]angiotensin II-induced phosphatidic acid formation. The diacylglycerol kinase inhibitor R59949 depressed [Sar1]angiotensin II-induced phosphatidic acid formation by only 21%, indicating that activation of a phospholipase C and diacylglycerol kinase also can not account for the bulk of phosphatidic acid. Thus, additional pathways not involving phospholipases C and D, such as de novo synthesis, may contribute to [Sar1]angiotensin II-induced phosphatidic acid in these cells. Finally, as previously shown for [Sar1]angiotensin II, phosphatidic acid stimulated mitogen activated protein (MAP) kinase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II induces phosphatidic acid formation in neonatal rat cardiac fibroblasts: evaluation of the roles of phospholipases C and D. 789 71

The regulation of diacylglycerol (DG) kinase activity was studied in fibroblasts and Jurkat T cells. We questioned whether enzyme activity only depends on substrate availability or whether it requires receptor stimulation. To this end, we raised DG levels up to 15-fold by treatment of cells with bacterial phosphatidylinositol-specific phospholipase C (PLC). In detergent cell lysates, DG kinase was readily capable of converting this surplus of DG to phosphatidic acid (PA), but in intact cells the enzyme remained inactive. Stimulation of fibroblasts with bradykinin or endothelin and Jurkat cells with anti-CD3 resulted in DG kinase-mediated formation of PA, but its level was unaffected by PLC pretreatment. Likewise, in streptolysin O-permeabilized fibroblasts, where bradykinin stimulation in the presence of [gamma-32P]ATP and guanosine 5'-O-(thiotriphosphate) generates [32P]PA exclusively via DG kinase, PLC pretreatment did not affect the amount of [32P]PA formed. We conclude that DG kinase acts on DG generated by receptor stimulation, but not on DG generated by exogenous PLC. We propose a model in which DG kinase physically associates with endogenous PLC. Within this complex, receptor-induced DG would then be transmitted ("channeled") from endogenous PLC to the active site of DG kinase, whereas excess DG generated randomly in the plasma membrane by bacterial PLC is inaccessible to this catalytic site.
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PMID:Diacylglycerol kinase in receptor-stimulated cells converts its substrate in a topologically restricted manner. 830 69


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