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)

Activation of adenosine A1-, bradykinin- or P2U-receptors on DDT1 MF-2 smooth muscle cells all increased the formation of inositol 1,4,5-trisphosphate and the mobilization of intracellular calcium. All three types of agents could increase [Ca2+]i in the same cell. Activation of the P2U receptor with ATP or UTP produced larger responses than activation of bradykinin- and adenosine A1-receptors, with bradykinin and N6-cyclopentyladenosine. When agonist-stimulated levels of diacylglycerol were determined, all agonists caused biphasic changes of similar magnitudes. If anything, ATP and UTP tended to give larger increases in the second phase of stimulation. Phospholipase D, measured as the formation of phosphatidylethanol in cells labeled with [3H]palmitic acid and activated in the presence of ethanol, was activated similarly as phospholipase C, i.e. ATP or UTP caused the largest increase in phosphatidylethanol formation, followed by N6-cyclopentyladenosine and bradykinin which caused weaker responses. Activation of PLD by P2U receptors was pertussis toxin insensitive. The activation of PLD by the agonists was only weakly affected by a PKC inhibitor, Ro 31-7549 (3-[1-(3-aminopropanyl)-3- indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione). In contrast, ATP or UTP did not activate protein kinase C, determined in a permeabilized cell assay using two specific protein kinase C substrates, whereas N6-cyclopentyladenosine and bradykinin caused a substantial activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of phospholipase C and phospholipase D by stimulation of adenosine A1, bradykinin or P2U receptors does not correlate well with protein kinase C activation. 777 Jan 1

Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that elicits a wide variety of responses in cells. TGF-beta binds to cell surface receptors that contain cytoplasmic serine/threonine kinase domains. Here we provide evidence that both phospholipase C and protein kinase C (PKC) are involved in the TGF-beta activation of transcription and luciferase expression from the p3TP-Lux plasmid. Down-regulation of PKC prevents TGF-beta 1 induction of luciferase expression. Staurosporin and Calphostin C, inhibitors of PKC, block the ability of TGF-beta 1 to initiate transcription of the luciferase gene. Further, D609, an inhibitor of phosphatidylcholine-phospholipase C (PC-PLC), and secondarily PKC also blocks TGF-beta 1-induced transcription of the transgene in A549 cells while the phosphatidylinositol-PLC pathway inhibitor U73122 is without effect. TGF-beta elevates steady-state mRNA levels for the endogenous PAI-1 and fibronectin genes. Treatment of cells with calphostin C or D609 prevents the TGF-beta-induced increase in these mRNAs. Together, these results suggest that PC-PLC and PKC are in a TGF-beta signaling pathway that results in elevated gene expression.
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PMID:Evidence for involvement of phosphatidylcholine-phospholipase C and protein kinase C in transforming growth factor-beta signaling. 777 10

Neutrophil (PMN) oxidant release, a key component of defenses against disseminated candidiasis, was preceded by oxidant generation after stimulation by Candida albicans hyphae. Opsonized or unopsonized hyphae triggered phospholipase D (PLD) activation within 5 or 30 s, respectively, forming 1-O-alkyl-phosphatidic acid (alkyl-PA) or 1-O-alkyl-phosphatidyl-ethanol in the presence of ethanol. Ethanol, which competitively lowers phosphatidic acid (PA) production, caused dose-dependent inhibition of superoxide (O2-) generation after hyphal stimulation but altered neither baseline-unstimulated O2- production nor responses to phorbol myristate acetate. PA rises evoked by unopsonized hyphae began 2 min before significant O2- release, also preceding both phospholipase C activation and cytosolic Ca2+ rises. Diacylglycerol (DAG) rose in two distinct phases after stimulation by opsonized or unopsonized hyphae, peaking briefly after 60 or 120 s, respectively, followed by prolonged secondary rises. Initial DAG rises preceded inositol triphosphate elevations evoked by unopsonized hyphae. Though PA rose before DAG, no dephosphorylation of PA to form 1-O-alkyl-DAG was noted. Propranalol, which increases PA accumulation by inhibiting PA phosphohydrolase, lowered PMN O2- responses to hyphae. Early DAG rises temporally overlapped respiratory burst initiation but PMN responses to hyphae were unchanged by a DAG kinase inhibitor, R59022, which blocks phosphorylation of DAG to PA and enhances DAG accumulation. Thus, neither PA nor DAG accumulation individually accounted for triggering PMN O2- responses to hyphae. PLD activation and PA production may facilitate PMN fungicidal responses to hyphae but play an indirect role in initiating the respiratory burst.
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PMID:Relationship of phospholipase C- and phospholipase D-mediated phospholipid remodeling pathways to respiratory burst activation in human neutrophils stimulated by Candida albicans hyphae. 779 Jul 66

The effects of progesterone and GTP gamma S on phospholipid N-methylation and sphingomyelin synthesis were studied in plasma-vitelline membranes isolated from amphibian (Rana pipiens) oocytes. Plasma-vitelline membranes were preincubated with S-adenosyl-L-[methyl-3H]methionine for 2 min at 20 degrees C and total phospholipids extracted at 0, 15, 30 and 60 s after addition of progesterone and/or GTP gamma S. Progesterone levels (3 microM) that induce meiosis in the intact oocyte stimulated [3H-methyl]incorporation into phosphatidylmonomethylethanolamine (PME) 9-10-fold over the first 60 s, with smaller increases in phosphatidyldimethylethanolamine (PDE) and phosphatidylcholine (PC). [methyl-3H] labeling of sphingomyelin (SM) rises after 30 s, approaching that of [methyl-3H]PME by 60 s. 17 beta-Estradiol, a noninducer of meiosis, was inactive. When oocytes were prelabeled with [3H]palmitic acid, it was found that a fall in [3H]ceramide coincides with the transient increase in [3H]SM, indicating that the end product of N-methylation (PC) undergoes a transfer reaction with ceramide to form SM and 1,2-DG. GTP gamma S levels previously reported to stimulate PC-specific phospholipase C activity in oocyte plasma membranes (5 microM) also stimulated both [methyl-3H]PME and [methyl-3H]SM formation. An inhibitor of phospholipid N-methylation, 2-(methyl-amino)ethanol, blocked stimulation of [methyl-3H]SM synthesis by both progesterone and GTP gamma S as well as induction of meiosis by progesterone. Progesterone thus acts at the oocyte plasma membrane to stimulate PE N-methyltransferase and SM synthase. The finding that GTP gamma S mimics progesterone suggests that N-methyltransferase is mediated by G-protein(s). The transient increase in 1,2-DG which we had previously reported to occur within 1-2 min following progesterone stimulation of the Rana oocyte appears to arise from PC by two different pathways: SM synthesis and hydrolysis of PC by phospholipase C.
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PMID:Progesterone-induced phospholipid N-methylation and sphingomyelin synthesis in the amphibian oocyte plasma membrane: a second source of the 1,2-diacylglycerol second messenger associated with the G2/M transition. 780 20

The effects of acute and chronic ethanol exposures on the stimulation of inositol specific phospholipase C by metabotropic glutamate receptor activation were determined in primary cultures of rat cortical astrocytes. Phospholipase C activity was monitored by the formation of [3H]inositol phosphates in the presence of lithium in cells prelabelled with [3H]inositol. Acute exposure to 200 mM ethanol had no significant effect on either basal or L-glutamate stimulated [3H]inositol phosphate formation. In cells chronically exposed to ethanol for 4 days, the [3H]inositol phosphate responses to L-glutamate, quisqualate, and the selective metabotropic receptor agonist, 1S,3R-1-amino-cyclopentane-1,3 dicarboxylic acid (trans-ACPD), were significantly inhibited when compared to control (untreated) cells. In contrast, chronic ethanol exposure had no significant effect on the [3H]inositol phosphate response to endothelin-1, a peptide structurally and functionally unrelated to L-glutamate. Similarly, the stimulation of [3H]inositol phosphate formation by the stable GTP analog, guanine 5'-(gamma-thiotrisphosphate), was also unaffected by chronic ethanol exposure. The results suggest that chronic ethanol exposure does not affect the coupling of GTP binding proteins to phospholipase C, but rather acts in a selective manner to either alter the metabotropic receptor number or to disrupt the normal coupling of this receptor to its GTP binding protein, which may in turn affect receptor affinity.
Alcohol
PMID:Selective effects of ethanol exposure on metabotropic glutamate receptor and guanine nucleotide stimulated phospholipase C activity in primary cultures of astrocytes. 781 99

In fibroblasts, the protein kinase C (PKC) activator phorbol 12-myristate (PMA) either inhibits or stimulates phospholipase C-mediated hydrolysis of phosphatidylethanolamine in the absence or presence of ethanol, respectively. Here, we demonstrate that the specific PKC inhibitor bisindolylmaleimide GF 109203X prevents only the inhibitory, but not the stimulatory, PMA effect.
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PMID:The bisindolylmaleimide GF 109203X, a selective inhibitor of protein kinase C, does not inhibit the potentiating effect of phorbol ester on ethanol-induced phospholipase C-mediated hydrolysis of phosphatidylethanolamine. 785 90

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

Interleukin 4 (IL-4) diminishes cytokine activation of human macrophage. IL-4 binding to monocyte IL-4R is associated with protein kinase C (PKC) translocation to a nuclear fraction. The cleavage of diacyglycerol (DAG), an activator of PKC, from membrane phospholipids was investigated to define the proximal events of IL-4R signaling. IL-4 induced a statistically significant time-and dose-dependent generation of DAG. The IL-4-triggered production of DAG was not derived from phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, since neither cytosolic calcium flux nor liberation of inositol phosphates was detected in response to IL-4. Experiments were performed using [14C-methyl]choline-labeled U937 cells and monocytes to determine whether IL-4R activated phospholipase C (PLC), PLD, or PLA2 to use membrane phosphatidylcholine (PC) to form DAG. IL-4 induced a time- and dose-dependent increase of phosphocholine (pchol) with concomitant degradation of membrane PC (p < 0.05 compared with control). The finding that the peak reduction of PC was equivalent to peak production of pchol suggested that IL-4R signaling involved the activation of a PC-specific PLC. Changes in choline (chol) or lyso-PC and glycerolphosphocholine, the respective products of PC cleavage by PLD or PLA2, were not detected in IL-4-treated cells. In contrast, exogenous PLD induced an increase in chol and concomitant loss of membrane PC. Additional investigation suggested that IL-4R signaling does not involve PLD. In cells labeled with L-lyso-3-PC 1-[1-14C]palmitoyl, PLD but not IL-4, increased the production of phosphatidic acid (PA) and phosphatidyl-ethanol when pretreated with ethanol. Propranolol, an inhibitor of phosphatidate phosphohydrolase, and calyculin A, a phosphatase 1 and 2A inhibitor, blocked DAG production in response to FMLP but not to IL-4. In propranolol pretreated cells, PMA but not IL-4 triggered the production of PA and lowered the amount of DAG. Evidence that PLA2 is not coupled to IL-4R is the detection of arachidonate production in response to FMLP but not to IL-4. Furthermore, IL-4R is not coupled to sphingomyelinase (SMase) since IL-4, unlike exogenous SMase, did not generate ceramide but induced the hydrolysis of PC to pchol that was comparable to exogenous PLC. In summary, IL-4R signaling in monocytes and U937 cells involves PLC and not PLD, PLA2, or SMase, and it uses PC and not PIP2 to form DAG.
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PMID:Interleukin 4 receptor signaling in human monocytes and U937 cells involves the activation of a phosphatidylcholine-specific phospholipase C: a comparison with chemotactic peptide, FMLP, phospholipase D, and sphingomyelinase. 793 Oct 78

Arginine vasopressin mediates its effects through vasopressin receptor activation and second messenger production. Recent cloning of the V1a receptor provided the opportunity to investigate the possible signal transduction pathways associated with this single vasopressin receptor subtype. When stably expressed in CHO cells, vasopressin stimulated several signal transduction pathways simultaneously including calcium influx, phospholipase A2, phospholipase C, and phospholipase D. Vasopressin-stimulated release of arachidonic acid, IP3 formation, and phosphatidylethanol formation (in the presence of 1% ethanol) were used as indexes of phospholipase A2, phospholipase C, and phospholipase D activation, respectively. V1a receptor-activation stimulated a peak followed by a sustained plateau phase of intracellular calcium. The plateau phase was dependent on extracellular calcium, insensitive to blockers of voltage sensitive calcium channels, blocked by heavy metals, and quenched when MnCl2 was present in the extracellular media. Removal of extracellular calcium blunted the release of IP3, and blocked the release of arachidonic acid and phosphatidylethanol indicating that these responses were at least in part regulated by receptor-operated calcium influx. Vasopressin-stimulated release of arachidonic acid and phosphatidylethanol were augmented with the phorbol ester PMA, and this augmentation was blocked by inhibitors of protein kinase C and absent with long-term PMA treatment. Vasopressin-stimulated IP3 release was inhibited with PMA and the inhibition reversed with protein kinase C inhibitors.
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PMID:The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. 796 20

The influence of dietary fat and alcohol on hepatic microsomal levels of cytochromes P-450 2E1, 2B, and 4A; phospholipases A and C; and UDP-glucuronosyltransferase was studied in the intragastric feeding rat model for alcoholic liver injury. Eight groups of animals were evaluated. Control and ethanol fed rats received either saturated fat or corn oil and were killed after 2 weeks and 1 month of feeding. All animals were pair-fed by continuous infusion of liquid diet through permanently implanted gastric cannulas. Alcoholic liver injury developed only in the corn oil-ethanol-fed groups and was manifest by 1 month. Livers were subjected to the following analyses: pathologic evaluation of liver injury; levels of cytochromes P-450 2E1, 2B, and 4A protein and mRNA; aniline hydroxylase activity; and phospholipase A and C and UDP-glucuronosyltransferase activities. Ethanol-induced increases in cytochromes P-450 2E1 and 2B protein determined by Western blotting were greatest in the corn oil-ethanol-fed group, which developed pathologic changes in the liver. Cytochromes P-450 2E1 and 2B1 mRNA levels were unaffected, suggesting that posttranscriptional mechanisms are responsible for the increase in the corresponding P-450 proteins. In contrast, cytochrome P-450 4A levels were higher in the saturated fat-ethanol groups compared with the corn oil-ethanol groups. Phospholipase A and phospholipase C levels were higher in the corn oil-ethanol groups compared with pair-fed dextrose controls and the saturated fat-ethanol groups. UDP-glucuronosyltransferase levels declined with time in the ethanol-fed groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Clin Exp Res 1994 Aug
PMID:Changes in cytochromes P-450, 2E1, 2B1, and 4A, and phospholipases A and C in the intragastric feeding rat model for alcoholic liver disease: relationship to dietary fats and pathologic liver injury. 797 3


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