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)

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are cytokines with pleiotropic biological activities, exerting a broad range of overlapping biological functions. The redundancy of TNF and IL-1 activities may be based on the utilization of shared key components of intracellular signaling pathways. Two lipid second messengers have been found to transmit TNF and IL-1 intracellular signals: 1,2-diacylglycerol (DAG), generated by a phosphatidylcholine-specific phospholipase C, and ceramide, generated by sphingomyelinase (SMase). DAG is a well established activator of the important signaling system protein kinase C (PKC), which appears to mediate various cellular responses to TNF or IL-1. In addition, it is obvious that DAG also activates other enzyme systems like acidic sphingomyelinase. SMases have been implicated in a number of TNF responses, including stimulation of cell growth and differentiation, as well as triggering cytotoxicity and apoptosis. The metabolic active cleavage product of SMase, ceramide, is a novel multifunctional lipid second messenger capable of inducing various signaling systems. Both cytokines, TNF and IL-1, stimulate a neutral,plasma membrane-associated SMase that leads to stimulation of a protein kinase and eventually to activation of the mitogen-activated protein (MAP) kinase cascade and phospholipase A2. Ceramide is also capable of stimulating a cytosolic protein phosphatase. PKC plays a role in activation of the nuclear transcription factor AP-1, and the DAG-regulated acidic SMase is involved in transducing TNF signals to the cell nucleus via activation of the nuclear transcription factor NF-kappa B.
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PMID:The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. 796 60

Carrot (Daucus carota L.) cells plasmolyzed within 30 s after adding sorbitol to increase the osmotic strength of the medium from 0.2 to 0.4 or 0.6 osmolal. However, there was no significant change in the polyphosphorylated inositol phospholipids or inositol phosphates or in inositol phospholipid metabolism within 30 s of imposing the hyperosmotic stress. Maximum changes in phosphatidylinositol 4-monophosphate (PIP) metabolism were detected at 5 min, at which time the cells appeared to adjust to the change in osmoticum. There was a 30% decrease in [3H]inositol-labeled PIP. The specific activity of enzymes involved in the metabolism of the inositol phospholipids also changed. The plasma membrane phosphatidylinositol (PI) kinase decreased 50% and PIP-phospholipase C (PIP-PLC) increased 60% compared with the control values after 5 min of hyperosmotic stress. The PIP-PLC activity recovered to control levels by 10 min; however, the PI kinase activity remained below the control value, suggesting that the cells had reached a new steady state with regard to PIP biosynthesis. If cells were pretreated with okadaic acid, the protein phosphatase 1 and 2A inhibitor, the differences in enzyme activity resulting from the hyperosmotic stress were no longer evident, suggesting that an okadaic acid-sensitive phosphatase was activated in response to hyperosmotic stress. Our work suggests that, in this system, PIP is not involved in the initial response to hyperosmotic stress but may be involved in the recovery phase.
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PMID:Changes in phosphatidylinositol metabolism in response to hyperosmotic stress in Daucus carota L. cells grown in suspension culture. 802 37

Prostaglandin G/H synthase (PGHS) is one of the key enzymes in prostaglandin synthesis. Regulation of the mRNA expression of the two isozymes PGHS-1 and PGHS-2 was investigated in mesangial cells. PGHS-1 was constitutively expressed and not modulated by any of the stimuli used. PGHS-2 was induced by the platelet products serotonin (5-HT) and thromboxane A2 (used as its analogue U46619), but not by ATP. Expression of PGHS protein was regulated correspondingly; whereas PGHS-1 protein was constitutively expressed, PGHS-2 protein was virtually absent in unstimulated cells, but could increasingly be induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), 5-HT, or fetal calf serum. Induction of PGHS-2 mRNA was transient with a peak after 2-3 h. Stimulated mRNA levels persisted for more than 6 h when transcription was inhibited by actinomycin D or when translation was inhibited by cycloheximide. As shown by specific inhibitors, 5-HT signal transduction was mediated by 5-HT2 receptors, which couple to phospholipase C via pertussis toxin-sensitive G-proteins. Induction of PGHS-2 mRNA by 5-HT was dependent on protein kinase C. Down-regulation of the enzyme by prolonged incubation with TPA abolished 5-HT-induced PGHS-2 mRNA expression. Short time activation of protein kinase C by TPA induced PGHS-2 mRNA expression. On the other hand, TPA given immediately before 5-HT decreased the 5-HT-induced PGHS-2 mRNA expression, indicating a negative feedback. The immunosuppressive drug cyclosporin A reduced induction of PGHS-2 mRNA expression by 5-HT, indicating interference with the signaling cascade, most likely with the Ser/Thr phosphatase calcineurin. Involvement of Tyr phosphorylation in 5-HT signaling was shown by the Tyr kinase inhibitor genistein, which inhibited the induction, while the Tyr phosphatase inhibitor vanadate by itself was able to induce PGHS-2 mRNA expression, which was further augmented when vanadate was combined with 5-HT. PGHS-2 mRNA expression is thus tightly regulated in mesangial cells and therefore allows modulation at various levels by physiological and pharmacological stimuli.
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PMID:Signal transduction pathways responsible for serotonin-mediated prostaglandin G/H synthase expression in rat mesangial cells. 808 94

Q10 values of the protein phosphatases that can dephosphorylate the regulatory light chain of smooth muscle myosin were determined. Six phosphatases were examined, i.e. skeletal muscle protein phosphatase 1c; protein phosphatase 2Ac; smooth muscle phosphatases (SMP) I, II, and IV; and myosin-associated protein phosphatase (MAP phosphatase). Among them, SMP-IV and MAP phosphatase, which can dephosphorylate intact smooth muscle myosin, showed extremely high Q10 values (5.3 and 5.2, respectively). On the other hand, the Q10 values of other tested phosphatases were within the range of the normal enzyme reaction (Q10 = 2.0). The rate of dephosphorylation of the myosin light chain in alpha-toxin-skinned strips was measured at different temperatures. The results provided a Q10 of 5.1, which was quite similar to those values obtained for SMP-IV and MAP phosphatase. These results suggest that the physiological myosin light chain phosphatases are SMP-IV and/or MAP phosphatase, i.e. type 1 protein phosphatases. The temperature dependence of maximum force, the steady-state extent of myosin light chain phosphorylation, and the relaxation rate of alpha-toxin-permeabilized rabbit portal vein smooth muscle strips were measured. Both maximum force and the extent of myosin light chain phosphorylation were significantly higher at lower temperature (15 degrees C) than at higher temperature (25 degrees C) under all pCa conditions tested, i.e. > 8, 6.3, and 5. The temperature dependence of the relaxation rate was much steeper (decreased 4 times by lowering the temperature from 25 to 15 degrees C) than that of the initial rate of increase in force development (decreased 1.4 times by lowering the temperature from 25 to 15 degrees C). These results are consistent with the Q10 values of myosin light chain phosphatases (Q10 = 5) and myosin light chain kinase (Q10 = 1.7) and further show that the smooth muscle type 1 phosphatases are responsible for the dephosphorylation of smooth muscle myosin in situ.
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PMID:Correlation between high temperature dependence of smooth muscle myosin light chain phosphatase activity and muscle relaxation rate. 811 26

The aim of this study was to investigate the stimulating effects of sulfhydryl reagents on glucose transport in isolated rat heart muscle cells and to compare them with the action of insulin. Low concentrations of the sulfhydryl oxidants hydrogen peroxide (H2O2) and diamide (5-100 microM), but also of phenylarsine oxide (PAO) (0.5-3 microM), that is known to specifically react with vicinal SH-groups, stimulated the rate of 2-deoxy-D-glucose uptake by a factor of 4 to 8 in these cells, while higher concentrations were inhibitory. The stimulating effects of H2O2 or diamide, and, to a significantly lesser extent, those of PAO or insulin, were depressed in cells pretreated with the sulfhydryl-alkylating agent N-ethylmaleimide (56-100 microM). H2O2 raised the Vmax and lowered the Km of 3-O-methyl-D-glucose uptake, while PAO or insulin solely increased Vmax. The increase in glucose transport caused by H2O2 was antagonized by the beta-adrenergic agonist isoprenaline (1 microM) or by a membrane-permeant cyclic AMP analog, whereas the effects of PAO or insulin were not altered. The action of H2O2 was additive with the stimulation induced by the protein phosphatase inhibitors okadaic acid (1 microM) or vanadate (6 mM), whereas the responses to PAO or insulin were reduced in the presence of these agents. Finally, H2O2 and PAO, but not insulin, acted additively with the protein kinase C ligand phorbol myristate acetate (0.8 microM) and with phospholipase C (0.03 units/ml). We conclude that, in cardiac myocytes, H2O2, on the one hand, and PAO (and possibly insulin), on the other hand, stimulate glucose transport via at least two distinct, SH-dependent pathways. These pathways, in turn, differ from a protein kinase C- and from a phospholipase C-mediated mechanism.
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PMID:Phenylarsine oxide and hydrogen peroxide stimulate glucose transport via different pathways in isolated cardiac myocytes. 824 Dec 56

Despite the differences in the antigens that they recognize and in the effector functions they carry out, B and T lymphocytes utilize remarkably similar signal transduction components to initiate responses. They both use oligomeric receptors that contain distinct recognition and signal transduction subunits. Antigen receptors on both cells interact with at least two distinct families of PTKs via common sequence motifs, ARAMs, in the cytoplasmic tails of their invariant chains, which have likely evolved from a common evolutionary precursor. Coreceptors appear to serve to increase the sensitivity of both of these receptor systems through events that influence ligand binding and signal transduction. The critical role of tyrosine phosphorylation of downstream signaling components, such as phospholipase C, is the net result of changes in the balance of the action of antigen receptor-regulated PTKs and PTPases. The identification of downstream effectors, including calcineurin and Ras, that regulate cellular responses, such as lymphokine gene expression, promises the future possibility of connecting the complex pathway from the plasma membrane to the nucleus in lymphocytes. Insight gained from studies of the signaling pathways downstream of TCR and BCR stimulation is likely to contribute significantly to future understanding of mechanisms responsible for lymphocyte differentiation and for the discrimination of self from nonself in developing and mature cells.
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PMID:Signal transduction by lymphocyte antigen receptors. 829 63

In pancreatic beta-cells, calcium is required for insulin secretion, but can also stimulate gene transcription. High potassium-induced membrane depolarization and calcium influx have previously been shown to activate kinases that phosphorylate and thereby activate the transcription factor cAMP response element (CRE-binding protein (CREB) binding to CREs. It is unknown, however, whether hormones and neurotransmitters can activate this mechanism. Arginine vasopressin (AVP), bombesin, and acetylcholine potentiate glucose-induced insulin secretion and are known to raise cytosolic calcium levels through binding to cell surface receptors that activate phospholipase C. The effect of AVP on CRE-directed transcription was examined in the beta-cell line HIT. AVP (0.1-100 nM) stimulated gene transcription after transient transfection of a reporter gene that was placed under the transcriptional control of a CRE. This effect was inhibited by a vasopressin V1 receptor antagonist and depended on calcium influx and calcineurin phosphatase activity. By immunoblots with antiphospho-CREB antibodies and by using a Gal4-CREB fusion protein, it was shown that AVP induces the phosphorylation and activation of CREB. Like AVP, bombesin (100 nM) and the muscarinic agonist carbachol (200 microM) stimulated CRE-mediated transcription. These results show that calcium-mediating insulin secretagogues can activate CREB/CRE-directed transcription in HIT cells, offering a mechanism by which these secretagogues could produce long term effects on beta-cell function, changing the pattern of gene expression.
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PMID:Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3',5'-monophosphate/calcium response element in a pancreatic islet beta-cell line. 853 17

Brush-border membrane vesicles (BBMV) were prepared from superficial rat renal cortex by a divalent(2+)-precipitation technique using either CaCl2 or MgCl2. The dependence of the initial [14C]-D-glucose (or [3H]-L-proline) uptake rate and the extent of the overshoot of D-glucose or L-proline uphill accumulation from solutions containing 100 mM Na+ salt, was found to be dependent upon the precipitating divalent cation. With Mg2+ precipitation the initial uptake and overshoot accumulation of either D-glucose or L-proline were enhanced compared to BBMV prepared by Ca2+ precipitation. When the anion composition of the media was varied (uptake in Cl- media in comparison to gluconate(-)-containing media) it was found that the Cl(-)-dependent component of the initial uptake was markedly depressed with Ca(2+)-prepared BBMV (104.99 +/- 33.31 vs. 13.83 +/- 1.44 pmoles/sec/mg protein for Mg2+ and Ca2+ prepared vesicles respectively). When Ca2+ was loaded into Mg2+ prepared BBMV using a freeze-thaw technique, it was found that the magnitude and Cl- enhancement of D-glucose transport was reduced in a dose-dependent manner. Neomycin, an inhibitor of phospholipase C, had no effect on the reduction of D-glucose uptake by Ca2+ in Mg2+ prepared vesicles. In contrast, phosphatase inhibitors such as vanadate and fluoride were able to partially reverse the Ca2+ inhibition of D-glucose uptake and restore the enhancement due to Cl- media. In addition, inhibitors of protein phosphatase 2B, deltamethrin (50 nM) and trifluoperazine (10 microM), caused partial reversal of Ca2(+)-dependent inhibition of D-glucose uptake. Direct measurement of changes in the bi-ionic (Cl-vs. gluconate-) transmembrane electrical potential differences using the cyanine dye, 3,3'-dipropylthiodicarbocyanine iodide DiSC3-(5) confirmed that Cl- conductance was reduced in Ca(2+)-prepared vesicles. We conclude that a Cl- conductance coexists with Na+ cotransport in rat renal BBMV and this may be subject to negative regulation by Ca2+ via stimulation of protein phosphatase (PP2B).
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PMID:An effect of Ca2+ on the Intrinsic Cl(-)-conductance of rat kidney cortex brush border membrane vesicles. 866 77

Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFRs) are ubiquitously expressed in the mammalian central nervous system, where they exert trophic actions on both neuronal and glial cells. However, the acute actions of PDGF on synaptic transmission are unknown. We report a novel regulatory action of PDGF/PDGFR. Activation of PDGFRs inhibited the function of native type A gamma-aminobutyric acid (GABAA) receptors (GABAA-RS) in rat hippocampal CA1 pyramidal neurons and mouse brain membrane vesicles. The mechanism of this inhibition was studied with a panel of mutant PDGFRS-beta coexpressed with cloned human GABAA-Rs in Xenopus oocytes. These experiments revealed that phospholipase C-gamma is the protein that relays the inhibitory signal from PDGFRS to GABAA-Rs. Experiments with microinjected EGTA and inositol-1, 3, 4-triphosphate demonstrated that inhibition of GABAA-Rs depended on a phospholipase C-gamma-mediated increase in intracellular Ca(2+)-levels. The PDGFR-induced inhibitory effect was independent of the subunit composition of GABAA-RS. Moreover, GABAA-RS composed of alpha 1 beta 1 S409A subunits, which do not contain any known protein kinase C phosphorylation sites, were inhibited by PDGF to the same extent as wild-type GABAA-RS. Inhibitors of protein kinase C, CA2+/calmodulin-dependent protein kinase II, calcineurin, and tyrosine phosphatases did not affect the modulatory actions of PDGFR. In conclusion, our results suggest that PDGFRs exert potent modulatory actions on GABAA-R-dependent inhibitory synaptic transmission. These regulatory actions of PDGF could play important roles in the function of the mammalian central nervous system during physiological and pathophysiological conditions.
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PMID:Platelet-derived growth factor receptor is a novel modulator of type A gamma-aminobutyric acid-gated ion channels. 884 10

The neurotrophins are signaling factors that are essential for survival and differentiation of distinct neuronal populations during the development and regeneration of the nervous system. The long-term effects of neurotrophins have been studied in detail, but little is known about their acute effects on neuronal activity. Here we use permeabilized whole-cell patch clamp to demonstrate that neurotrophin-3 (NT-3) and nerve growth factor activate calcium-dependent, paxilline-sensitive potassium channels (BK channels) in cortical neurons. Application of NT-3 or nerve growth factor produced a rapid and gradual rise in BK current that was sustained for 30-50 min; brain-derived neurotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor-1 had no significant effect. The response to NT-3 was blocked by inhibitors of protein kinases, phospholipase C, and serine/threonine protein phosphatase 1 and 2a. Omission of Ca2+ from the extracellular medium prevented the NT-3 effect. Our results indicate that NT-3 stimulates BK channel activity in cortical neurons through a signaling pathway that involves Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent. Activation of BK channels may be a major mechanism by which neurotrophins acutely regulate neuronal activity.
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PMID:Activation of calcium-dependent potassium channels in mouse [correction of rat] brain neurons by neurotrophin-3 and nerve growth factor. 902 72


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