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)

The effect of bradykinin on the activation production of inositol 1,4,5-trisphosphate and prostaglandin E2 (PGE2) was examined in the murine osteoblastic cell line, MC3T3-E1. Bradykinin, at concentrations ranging from 1 to 1000 nM, stimulated the production of inositol 1,4,5-trisphosphate 2.5- to 3-fold within 10 s, and elevated cytosolic-free Ca2+, even in the absence of external Ca2+. This process is mediated through the activation of phospholipase C. Bradykinin at the same concentration also stimulated the production of PGE2 and caused a release of 3H radioactivity from the cells prelabeled with [3H]arachidonic acid, probably via the activation of phospholipase A2. Pretreatment of the cells with pertussis toxin inhibited the stimulation of PGE2 production and 3H radioactivity release, while the elevation in cytosolic Ca2+ and the production of inositol 1,4,5-trisphosphate were not altered by toxin-pretreatment. The addition of an unhydrolyzable analog of GTP, guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) to the beta-escin-permeabilized cells prelabeled with [3H]arachidonic acid enhanced the release of 3H radioactivity. The simultaneous presence of bradykinin with GTP gamma S further activated the 3H radioactivity release in the beta-escin-permeabilized cells. These results provide evidence that receptors for bradykinin in the MC3T3-E1 couple stimulating arachidonate release, probably via the activation of phospholipase A2, through a guanine nucleotide binding protein sensitive to pertussis toxin.
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PMID:Evidence for coupling of bradykinin receptors to a guanine-nucleotide binding protein to stimulate arachidonate liberation in the osteoblast-like cell line, MC3T3-E1. 165 14

We observed that in hypoxic myocardial cells prostacyclin and arachidonic acid release increased and that during hypoxia phospholipid degradation also occurred. In order to clarify the mechanism of phospholipid degradation, we determined the activity of phospholipases A2 and C. We found that phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were markedly decreased and that lysophosphatidylcholine and lysophosphatidylethanolamine were increased. In contrast, there was only slight phosphatidylinositol degradation and no lysophosphatidylinositol elevation was observed. These results show that phospholipase A2 was activated in hypoxic myocytes and had substrate specificity towards PC and PE. To study phospholipase C activity, membrane phospholipids were labeled with [3H]choline, [3H]inositol or [3H]ethanolamine. The release of inositol was observed, but neither choline nor ethanolamine was released. In hypoxia, myocardial-cell phospholipase C has high substrate specificity towards phosphatidylinositol. The activation of phospholipases is closely related to the intracellular Ca2+ concentration; it is though that inositol polyphosphatides may regulate intracellular Ca2+. We determined how Ca2+ influx occurs in hypoxia. beta-Adrenergic blockade and Ca2+ antagonists markedly suppressed Ca2+ influx, phospholipase A2 activity, phospholipase C activity and cell death. However, the alpha 1-adrenergic blockade was less effective in suppressing these phenomena. These results suggest that in hypoxic myocardial cells Ca2+ influx mediated by beta-adrenergic stimulation activates phospholipases A2 and C, and that phospholipid degradation and prostacyclin release then occur.
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PMID:Phospholipid metabolism and prostacyclin synthesis in hypoxic myocytes. 165 15

FRTL-5 thyroid cells express a muscarinic receptor which inhibits the phospholipase C activity in a pirenzepine-insensitive manner. We here report that the cholinergic agonist carbachol decreases in these cells the steady-state iodide content, an effect correlated with the iodination of thyroglobulin and with thyroid hormone formation. Several signal pathways may be involved in this phenomenon since carbachol in addition to inhibiting phospholipase C, increased the arachidonic acid release and modified the adenylyl cyclase activity. In FRTL-5 cells, arachidonic acid is released via the direct stimulation of phospholipase A2 by a pirenzepine-sensitive muscarinic receptor coupled to a GTP binding protein sensitive to pertussis toxin. Regarding adenylyl cyclase, carbachol potentiated the thyrotropin-induced stimulation of the enzyme, whereas it did not affect the basal levels of cAMP. In vitro binding studies revealed the presence of two muscarinic binding sites. To summarize, the analysis of signal pathways and of in vitro binding sites indicates a complex muscarinic regulation of thyroid function, which includes the modulation of iodide fluxes.
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PMID:Muscarinic regulation of phospholipase A2 and iodide fluxes in FRTL-5 thyroid cells. 165 22

Two cell lines transformed by the k-ras oncogene (KiKi and KiMol cells) and a temperature sensitive clone (Ts), all originated from a normal rat thyroid line (FRTL5 cells), have been employed to analyse the intracellular mechanisms affected by the ras p21. In k-ras transformed cells two phosphoinositide derivatives, glycerophosphoinositol and inositol monophosphate, were markedly increased, whereas inositol bisphosphate and trisphosphate maintained the same level as in normal cells. Cytosolic Ca2+ was also unaffected. This indicates that in epithelial cells the phospholipase C activity is not altered upon ras transformation. The formation of glycerophosphoinositol involved the activation of a phosphoinositide specific phospholipase A2. The higher phospholipase A2 activity in ras transformed cells could be further demonstrated by the increase in total arachidonic acid release. In the Ts clone the increase in glycerophosphoinositol and inositol monophosphate was evident only at the permissive temperature (33 degrees C), whereas it disappeared at 39 degrees C. At 33 degrees C the cells were also characterized by an enriched membrane pool of phosphoinositides. All these changes occurred in parallel with morphological transformation. We propose that cell transformation by the k-ras oncogene affects different steps of the membrane lipid metabolism, among which the most prominent one is the activation of a phosphoinositide specific phospholipase A2. These effects could originate mitogenic metabolites. Moreover, they correlate well with the induction of the malignant phenotype.
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PMID:Transformation by the k-ras oncogene correlates with increases in phospholipase A2 activity, glycerophosphoinositol production and phosphoinositide synthesis in thyroid cells. 165 98

We explored the nature and time course of the multiple signal transduction pathways for V1-vascular vasopressin (AVP) receptors of A7r5 aortic smooth muscle cells in culture by using radioligand binding techniques, intracellular calcium monitoring, and polyphosphoinositide and phospholipid analyses. V1-vascular AVP receptors of A7r5 cells were characterized by the agonist radioligand [3H]AVP and the antagonist radioligand [3H]d(CH2)5Tyr(Me)AVP. Affinity and capacity of agonist but not antagonist binding were modulated by MgCl2 and aluminum fluoride, suggesting that the receptors are coupled to a guanine nucleotide regulatory protein. In fura-2-loaded A7r5 cells, AVP induced within seconds a dose-dependent increase of free intracellular Ca++ ([Ca++]i) consisting of a rapid transient spike and a sustained increase lasting for 3-5 min. The baseline [Ca++]i was 136 +/- 18 nM, the maximum [Ca++]i response to AVP was 1,582 +/- 297 nM, and AVP ED50 was 1.87 +/- 0.15 nM. Diverse experiments performed with EGTA, 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethylester, Mn++, ionomycin, terbutylbenzo hydroquinone, and nicardipine suggested that the initial spike resulted from both intracellular Ca++ release from the endoplasmic reticulum and extracellular Ca++ influx, whereas the sustained phase depended on dihydropyridine-insensitive extracellular Ca++ influx. Experiments done with indomethacin and arachidonic acid indicated that AVP-induced extracellular Ca++ influx was in part dependent on phospholipase A2 activation. In [3H]myoinositol and [3H]arachidonate-labeled A7r5 cells, AVP stimulated inositol 1,4,5 trisphosphate and 1,2 diacylglycerol production via activation of phospholipase C. Also, AVP stimulated a transphosphatidylation reaction through activation of phospholipase D in A7r5 cells labeled with [3H]1-O-alkyl lysoglycerophosphocholine. Thus, the stimulation of V1-vascular AVP receptors of A7r5 cells triggers several signaling pathways. The immediate and transient [Ca++]i rise due to mobilization of intracellular and extracellular Ca++ is associated with the activation of phospholipases A2 and C, and the sustained activation of phospholipase D.
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PMID:Multiple signaling pathways of V1-vascular vasopressin receptors of A7r5 cells. 165 17

We have determined the concentration of free fatty acids in membranes of slices prepared from the dentate gyrus following the induction of long-term potentiation in the anaesthetized rat. Compared to unpotentiated tissue, there was a significant increase in the concentration of free arachidonic acid 2.5 min, 45 min and 3 h after induction of long-term potentiation. There was no corresponding increase in oleic, stearic or palmitic acids. To account for the increase in free arachidonate, the activities of phospholipase A2, phospholipase A1 and phospholipase C were determined at the same three time intervals in control and potentiated tissue. Two-and-a-half minutes after the induction of long-term potentiation, activity of phospholipase A2 was enhanced, while at 45 min, and at 3 h phospholipase C activity was increased. These results suggest that the liberation of free arachidonate is due initially to phospholipase A2 activity, but that at later stages of long-term potentiation, control switches to phospholipase C. Subcellular fractionation experiments revealed an increase in free arachidonate in the postsynaptic density fraction 45 min after induction of long-term potentiation, without significant changes in synaptosomal- or glial-enriched fractions. These results are consistent with the hypothesis that arachidonic acid, released from a postsynaptic site, acts as a trophic retrograde synaptic signal in long-term potentiation in the dentate gyrus.
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PMID:Increase in arachidonic acid concentration in a postsynaptic membrane fraction following the induction of long-term potentiation in the dentate gyrus. 166 36

Platelet activation begins with the binding of an agonist to the cell surface and culminates in the events of platelet aggregation, secretion and clot formation. Recent studies have identified two large families of GTP-binding proteins in platelets that are thought to participate in the events of platelet activation. The first of these are the G proteins, heterotrimeric proteins which are best known for their ability to mediate the interaction between agonist receptors and intracellular enzymes such as adenylyl cyclase, phospholipase C and phospholipase A2. To date, at least six G proteins have been identified in platelets: Gs, Gz, three variants of Gi and either Gq or G11 (or both). An additional, pertussis toxin-resistant G protein, Gq, may also be present. The second group of GTP-binding proteins present in platelets is substantially smaller than the heterotrimeric G proteins, ranging in size from 21 to 28 kDa. At least 15 such low molecular weight GTP-binding proteins have been identified in platelets, many of which are homologous to the products of the ras proto-oncogenes. In cells other than platelets, low molecular weight GTP-binding proteins have been implicated in protein transport, cell activation events and malignant transformation. Their role in platelets is unknown.
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PMID:The role of GTP-binding proteins in platelet activation. 166 93

Snake venom cardiotoxin (CTX) fractions induce contractures of skeletal muscle and hemolysis of red blood cells. The fractions also contain trace amounts of venom-derived phospholipase A2 (PLA2) contamination and activate tissue phospholipase C (PLC) activity. The present study examines the mechanisms of action of a CTX fraction from Naja naja kaouthia venom in skeletal muscle. Sphingosine competitively antagonized CTX-induced red blood cell hemolysis, but not skeletal muscle contractures. CTX rapidly lowered the threshold for Ca(2+)-induced Ca2+ release in heavy sarcoplasmic reticulum fractions, as monitored with arsenazo III. There was also a slower time-dependent reduction of Na+ currents, as assessed by whole cell patch-clamp techniques. The CTX fractions elevated levels of free fatty acids and diacylglycerol for 2 hr in primary cultures of human skeletal muscle by a combined action of venom-derived PLA2 contamination in the fraction and activation of endogenous PLC activity. The activation of tissue PLC activity could be readily distinguished from the contribution of the venom PLA2 by p-bromophenacyl bromide treatment of CTX fractions. The mechanism of action involved in contractures of skeletal muscle appears to be related to the immediate and specific effect of CTX (Ca2+ release by the sarcoplasmic reticulum), while the mechanisms involved in hemolysis of red blood cells and decreased Na+ currents in skeletal muscle most likely relate to long-term effects on lipid metabolism.
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PMID:Effects of a cardiotoxin from Naja naja kaouthia venom on skeletal muscle: involvement of calcium-induced calcium release, sodium ion currents and phospholipases A2 and C. 166 2

When a blood vessel is disrupted, subendothelial structures such as collagen come into contact with circulating blood platelets. These will adhere and recruit additional platelets to form a platelet aggregate which will close the leak, but which can, under certain circumstances, give rise to the formation of a thrombus. In this work our personal contribution to a better understanding of this process is given. We could demonstrate the presence of an antibody interfering with the platelet-collagen interaction in two patients with a bleeding problem. One of the antibodies is directed against glycoprotein (GP) Ia, a known collagen receptor, the other one recognizes a less well characterized protein of 85-90 kD. It therefore can be concluded that activation of blood platelets requires the simultaneous interaction of collagen with multiple receptors. Activation of platelets following binding of an agonist in many instances involves activation of phospholipase C via a GTP-binding protein or G-protein. We have further studied this by using a direct stimulator of G-proteins, AlF4-, which in platelets indeed activates phospholipase C, together with other systems. Furthermore, we could demonstrate that activation of phospholipase C in a GTP-dependent manner also occurs in platelet cytosol, indicating that the action of G-proteins is not restricted to membrane-linked phenomena. Activation of phospholipase C gives rise to the formation of inositol phosphates, of which mainly inositol 1, 4, 5 trisphosphate increases intracellular Ca(2+)-levels. Following this, the Ca(2+)-dependent phospholipase A2 releases arachidonic acid from the membranes. In platelets arachidonic acid is metabolised to another platelet activator: thromboxane A2. We have studied the effects of the inhibition of this aggregation-amplifying pathway by using specific inhibitors of the synthesis of thromboxane A2 and of thromboxane A2 receptor antagonists both in vitro and in vivo. One of the conclusions that were reached from these studies was that theoretically the combination of these two classes of drugs should yield a significant stronger antiplatelet effect than either class used alone. We could later on confirm this hypothesis, which stimulated some pharmaceutical companies to look for dual action compounds, of which we have studied two so far.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Signal transduction in blood platelets]. 166 33

Rat basophilic leukemia (RBL 2H3) cells were passively sensitized by exposure to monoclonal anti-trinitrophenol mouse immunoglobulin E (anti-trinitrophenol IgE) (0.5 microgram/ml) and triggered by exposure to a sub-optimal concentration of trinitrophenol ovalbumin conjugate (5 ng/ml). At this concentration, trinitrophenol-ovalbumin increased histamine release from a basal rate of 4.8 +/- 0.5 to 28.5 +/- 4.6% and peptidoleukotrienes from less than 0.1 to 4.2 +/- 1.3 ng/10(6) cells in the activated cells. Ro 19-3704 and Ro 19-1400, platelet activating factor (PAF) antagonists which are structural analogs of PAF, potently inhibited both the IgE-dependent release of histamine (IC50 values of 3.0 and 3.6 microM, respectively) and LT release (IC50 values of 5.0 microM for both compounds) from the cells. These effects appeared to be independent to the ability of the compounds to act as PAF antagonists since PAF on its own had no effect on mediator release, and WEB 2086 and BN 52021, structurally distinct PAF antagonists, were relatively ineffective as inhibitors of mediator release. Ro 19-3704 and Ro 19-1400 were observed to be potent inhibitors of the soluble phospholipase A2 activity in synovial fluid from rheumatoid arthritic patients (IC50 values of 6.5 and 8.4 microM, respectively). In contrast, WEB 2086 and BN 52021 had no effect on this phospholipase A2. Ro 19-3704 significantly inhibited the IgE-dependent formation of inositol phosphates in RBL 2H3 cells (IC50 value of 7.0 microM). These data suggest that the mediator release inhibitory action of these compounds may be related to the ability of these compounds to inhibit phospholipase A2 and/or phospholipase C.
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PMID:Ro 19-3704 directly inhibits immunoglobulin E-dependent mediator release by a mechanism independent of its platelet-activating factor antagonist properties. 169 11


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