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

---

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

Activation of platelets is correlated with phospholipase C-induced degradation of phosphatidylinositol 4,5-bisphosphate and the rapid formation of 1,2-diacylglycerol and myo-inositol 1,4,5-trisphosphate. Both products are considered second messengers and they, respectively, stimulate protein kinase C and Ca2+ mobilization. Mobilization of Ca2+ leads to activation of a Ca2+/calmodulin-dependent myosin light chain kinase and phospholipases A2 which liberate arachidonic acid from phospholipids. Arachidonate is then immediately converted to active endoperoxides and thromboxanes which are released and activate further platelets again through phospholipase C. The levels of phosphatidic acid and lysophosphatidic acid are also increased following receptor-stimulated hydrolysis of the inositol phospholipids. Lysophosphatidic acid might have a direct action on the opening of Ca2+-channels.
...
PMID:Relative importance of diacylglycerol, phosphatidate, lysophosphatidate, inositol trisphosphate and arachidonate metabolism in platelet receptor signalling. 299 3

The Ca2+ ionophore A23187 (0.2-5 microM) stimulates the phosphorylation of the substrates of protein kinase C (40,000 dalton protein) and myosin light chain kinase (20,000 dalton protein) in the presence or absence of cyclooxygenase inhibitors. In the presence of cyclooxygenase inhibitors or millimolar Ca2+ there is no stimulation of phospholipase C by A23187. Fingerprints of the 32P-labeled 40,000 dalton protein isolated from platelets that have been stimulated with A23187, thrombin, phorbol 12,13-dibutyrate and 1,2-didecanoylglycerol were identical. Higher concentrations of A23187 (1-5 microM) induced the loss of polyphosphoinositides through phosphomonoesterase activity.
...
PMID:Ionophore A23187 stimulates phosphorylation of the 40,000 dalton protein in human platelets without phospholipase C activation. 301 50

Inositol 1,4,5-trisphosphate induces aggregation and the release of [3H]5-hydroxytryptamine from human platelets rendered permeable with saponin. This action of inositol 1,4,5-trisphosphate is associated with a significant formation of thromboxane B2, activation of phospholipase C, and phosphorylation of 20,000- and 40,000-dalton proteins, which are the substrates for myosin light chain kinase and protein kinase C, respectively. All of these responses are blocked by the cyclooxygenase inhibitors indomethacin and aspirin and the dual cyclooxygenase and lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C). These data indicate that platelet activation by inositol 1,4,5-trisphosphate is initiated by the mobilization of Ca2+, which leads to phospholipase A2 activation. The thromboxanes and endoperoxides that are subsequently generated then induce activation via cell surface receptors.
...
PMID:Inositol 1,4,5-trisphosphate induces aggregation and release of 5-hydroxytryptamine from saponin-permeabilized human platelets. 308 84

A maximally effective dose of indomethacin does not prevent serotonin release and aggregation in human platelets stimulated with thrombin. Thrombin induces rapid activation of inositol phospholipids-specific phospholipase C, which is reflected by the degradation of inositides and the phosphorylation of the resultant 1,2-diacylglycerol to phosphatidic acid. Thrombin also activates protein kinase C and myosin light chain kinase as indicated by phosphorylation of the 40,000 and 20,000 dalton proteins, respectively. Leupeptin, a protease inhibitor that does not inhibit thrombin's proteolytic activity or its binding to platelet surface, is able to reverse platelet activation by thrombin when it is administered after the addition of the agonist and indomethacin. The results suggest a proteolytic-mediated pathway in transmembrane signalling involved in platelet activation by thrombin.
...
PMID:Sustained proteolysis is required for human platelet activation by thrombin. 371 2

Thrombin and trypsin induce serotonin release and aggregation in human platelets. Both proteases induce activation of phospholipase C as reflected by formation of inositol phosphates and phosphorylation of the resultant 1,2-diacylglycerol to phosphatidic acid. Also, thrombin and trypsin activate protein kinase C and myosin light chain kinase as indicated, respectively, by phosphorylation of the 40,000 and 20,000 dalton proteins. Leupeptin, a known inhibitor of serine proteases, blocks all the observed responses of human platelets to trypsin and thrombin. Leupeptin does not inhibit serotonin release and aggregation induced by other platelet stimuli such as collagen, platelet-activating factor, ionophore A23187, and arachidonic acid. The implication of a proteolytic-mediated pathway in the transmembrane signalling involved in platelet activation is discussed.
...
PMID:Leupeptin selectively inhibits human platelet responses induced by thrombin and trypsin; a role for proteolytic activation of phospholipase C. 405 85

KRDS, a tetrapeptide from human lactotransferrin, inhibits thrombin-induced platelet aggregation, secretion and thromboxane (TX) synthesis without interfering with phospholipase C (PLC) beta activation, since in previous work we have shown that Ca2+ mobilization and phosphorylation of the myosin light chain kinase (20 kDa) and pleckstrin (47 kDa) were normal. However, the inhibition of arachidonic acid-induced aggregation in the presence of KRDS is accompanied by normal TX synthesis suggesting that it does not interfere with the cyclooxygenase activity. To elucidate further the mechanisms of action of this peptide we tested its effect on U46619-induced platelet activation. KRDS inhibits U46619-induced platelet aggregation time- and dose-dependently without inhibiting the phosphorylation of pleckstrin. This suggests that the PLC pathway is not affected and that the inhibitory effect of KRDS is not due to and uncoupling of TXA2 from its receptor. In addition to the PLC pathway, protein tyrosine kinases play a major role in platelet signal transduction mechanisms. At least 7 tyrosine-phosphorylated proteins are detected upon stimulation of platelets by thrombin. KRDS strongly inhibits the tyrosine-phosphorylated substrates, in particular two 100-105 kDa substrates which are related to GP IIb/IIIa activation and platelet aggregation. The absence of TX synthesis observed in the presence of KRDS could be due to the inactivation of cPLA2 since the latter needs tyrosine phosphorylation to be activated, thus explaining the inhibitory action of KRDS on platelet functions.
...
PMID:KRDS, a peptide derived from human lactotransferrin, inhibits thrombin-induced thromboxane synthesis by a cyclooxygenase-independent mechanism. 748 16

The effects of U-73122, a phospholipase C (PLC) inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), BAY K 8644, and the thromboxane A2 (TxA2) mimic, U-46619, were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and the calcium channel opener, BAY K 8644, into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure, which were reproducible with respect to time. Infusion of U-73122, a PLC inhibitor, into the perfused lobar artery at 10-100 micrograms/kg for 10 min significantly reduced responses to ANG II, serotonin, and NE; however, U-73122 did not alter responses to BAY K 8644 or to U-46619. In a separate series of animals, the effects of the myosin light chain kinase inhibitor, KT-5926, were investigated, and after infusion of KT-5926 into the perfused lobar artery at 1-2 micrograms/kg for 10 min, responses to ANG II, NE, 5-HT, BAY K 8644, and U-46619 were reduced significantly. In a final series of experiments, the effects of the L-type calcium channel blocker, nicardipine, were investigated, and infusion of the L-type calcium channel blocker into the perfused lobar artery at 0.5-1 microgram/kg for 10 min reduced responses to ANG II, BAY K 8644, and NE. However, nicardipine did not alter pressor responses to 5-HT or the TxA2 mimic, U-46619.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Influence of PLC and MLCK inhibitors and the role of L-calcium channels in the cat pulmonary vascular bed. 748 23

The permeability to high molecular weight (IgG, 150 kD) proteins of the plasma membrane of receptor-coupled smooth muscles permeabilized with beta-escin was determined using confocal microscopy of immunofluorescent tracers and measurement of lactate dehydrogenase (LDH, 135-140 kD) leakage. Permeabilized strips of rabbit portal vein and guinea pig ileum were incubated in a relaxing solution containing mouse anti-smooth muscle alpha-actin antibody and immunostained with F(ab')2 labeled with tetramethyl rhodamine isothiocyanate. Confocal light microscopy of Triton X-100 and beta-escin permeabilized cells showed homogeneous staining of the cytoplasm, whereas in alpha-toxin treated and intact preparations only damaged cells at the edges of the strips were stained. Both the Ca(2+)-sensitizing effect of phenylephrine, in rabbit portal vein, and Ca2+ release by carbachol in guinea pig ileum, were retained after permeabilization and the treatment with the primary antibody. During the 30 min permeabilization, 38%, and within the next 75 min an additional approximately 30%, of the total LDH leaked out from the beta-escin-treated group, but not from the alpha-toxin-treated group (3.2%). The responsiveness to agonist and maximum contractility was improved if the preparations were incubated during the introduction of proteins at 4 degrees C, rather than 24 degrees C. Ca(2+)-independent myosin light chain kinase (61 kD) contracted the permeabilized portal vein in the absence of free Ca2+ (pCa < 8). In conclusion, permeabilization with beta-escin allows the transmembrane passage of 150 kD proteins under our experimental conditions that also retain receptor-coupled signal transduction.
...
PMID:Introduction of high molecular weight (IgG) proteins into receptor coupled, permeabilized smooth muscle. 771 37

Haemorrhagic diatheses due to platelet function defects are a heterogenous and poorly understood group of conditions. We report the investigation of a female with a lifelong history of epistaxes, haemarthroses, menorrhagia and persistent iron-deficiency anaemia. Although platelet numbers and morphology were normal, platelet function was abnormal both in vivo and in vitro. Skin bleeding time was prolonged and aggregation thresholds in platelet-rich plasma to a variety of weak and strong agonists were increased. Platelet granule contents were normal and membrane glycoproteins GpIb and GpIIIa were present in normal amounts. Polyphosphoinositide metabolism and phosphatidic acid generation were diminished in thrombin-stimulated platelets, as was phosphorylation of the 47 kD substrate for protein kinase C and the 20 kD protein myosin light chain kinase, indicating impaired generation of the intracellular second messengers diacylglycerol and inositol trisphosphate due to diminished stimulated phospholipase C activity. Although intracellular free calcium, calmodulin activity and basal cAMP concentrations were normal, washed platelets showed increased cAMP accumulation following stimulation with prostaglandin E1 and forskolin. Platelet membrane lipid analysis revealed a reduction in plasmalogen phosphatidylethanolamine content. It is suggested that the membrane phospholipid abnormalities cause the abnormal platelet reactivity by interfering with signal transduction from platelet receptor, via intermediary G proteins, to phospholipase C and adenylate cylase. The bleeding tendency is likely to be a consequence of the altered stimulus-response coupling.
...
PMID:A haemorrhagic platelet disorder associated with altered stimulus-response coupling and abnormal membrane phospholipid composition. 780 35

To examine their role in insulin secretion, actin filaments (AFs) were disrupted by Clostridium botulinum C2 toxin that ADP-ribosylates G-actin. Ribosylation also prevents polymerization of G-actin to F-actin and inhibits AF assembly by capping the fast-growing end of F-actin. Pretreatment of HIT-T15 cells with the toxin inhibited stimulated insulin secretion in a time- and dose-dependent manner. The toxin did not affect cellular insulin content or nonstimulated secretion. In static incubation, toxin treatment caused 45-50% inhibition of secretion induced by nutrients alone (10 mM glucose + 5 mM glutamine + 5 mM leucine) or combined with bombesin (phospholipase C-activator) and 20% reduction of that potentiated by forskolin (stimulator of adenylyl cyclase). In perifusion, the stimulated secretion during the first phase was marginally diminished, whereas the second phase was inhibited by approximately 80%. Pretreatment of HIT cells with wartmannin, a myosin light chain kinase inhibitor, caused a similar pattern of inhibition of the biphasic insulin release as C2 toxin. Nutrient metabolism and bombesin-evoked rise in cytosolic free Ca2+ were not affected by C2 toxin, indicating that nutrient recognition and the coupling between receptor activation and second messenger generation was not changed. In the toxin-treated cells, the AF web beneath the plasma membrane and the diffuse cytoplasmic F-actin fibers disappeared, as shown both by staining with an antibody against G- and F-actin and by staining F-actin with fluorescent phallacidin. C2 toxin dose-dependently reduced cellular F-actin content. Stimulation of insulin secretion was not associated with changes in F-actin content and organization. Treatment of cells with cytochalasin E and B, which shorten AFs, inhibited the stimulated insulin release by 30-50% although differing in their effects on F-actin content. In contrast to HIT-T15 cells, insulin secretion was potentiated in isolated rat islets after disruption of microfilaments with C2 toxin, most notably during the first phase. This effect was, however, diminished, and the second phase became slightly inhibited when the islets were degranulated. These results indicate an important role for AFs in insulin secretion. In the poorly granulated HIT-T15 cells actin-myosin interactions may participate in the recruitment of secretory granules to the releasable pool. In native islet beta-cells the predominant function of AFs appears to be the limitation of the access of granules to the plasma membrane.
...
PMID:Effect of disruption of actin filaments by Clostridium botulinum C2 toxin on insulin secretion in HIT-T15 cells and pancreatic islets. 786 85


<< Previous 1 2 3 4 5 6 Next >>

---