Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins are the products of cyclo-oxygenase and endoperoxide breakdown of free intracellular arachidonic acid (AA). Arachidonic acid is cleaved from membrane phospholipids by phospholipase A2 (PLA2) and phospholipase C (PLC). The human placenta is a rich source of lipocortin like PLA2 inhibitors. Human endometrium contains both PLA2 and PLC activity, and it is under research which pathway is predominant. Prostaglandin F2-alpha is derived from PLC endoperoxide, while prostaglandin E2 is formed by degradation of PG endoperoxide. Dated studies have found that prostaglandin F2-alpha was the predominant PG in the endometrium, whereas concentrations of PGE2 did not change during the cycle. In women estradiol stimulates PG synthesis from glands, and it has a role in mediating intracellular calcium in the human. Progesterone reduces the release of PGs from endometrial explants maintained in culture, while anti-progestins RU486 and ZK98734 stimulate the release of PGs from glandular cells of decidua. There seems to be a direct effect of progesterone on expression of PG synthetase, on the expression of a PG synthesis inhibitory protein, or an effect on a PLA2 activating protein. ZK98734 does not alter the metabolism of PGF2-alpha in the absence of added AA. Calmodulin also plays a role in regulating PG synthesis. Verapamil suppresses basal release of PGF2-alpha and prevents the rise in PG release caused by ZK98734. Progesterone suppresses PG synthesis in human endometrium. Colony stimulating factor- 1 (CSF-1) stimulates Ishikawa cell proliferation, acts on the hemopoietic system, and promotes the release of cytokines like interleukin-2, tumor necrosis factor (TNF), and interferons. Transforming growth factor alpha (TGF-alpha) mediates wound healing by promoting epithelial proliferation and angiogenesis and repairs desquamated endometrium. Epidermal growth factor (EGF) is present in the luminal surface of epithelial cells and myometrium but not in stromal cells. EGF p[lays a role in the proliferation of human endometrium and steroids modify this effect. INsulin-like growth factor (IGF-1) potentiates the activities of other mitogens like EGF. Basic fibroblast growth factor (bFGF) and acidic FGF (aFGF) have been detected in the uterine flushings and tissue of the guinea pig. FGF is a mediator of angiogenesis. different PGs affect vascular contractility, hemostasis, and myometrial contractility. PG synthesis is linked to menstrual dysfunction. The functions of growth factors and PGs may be related reflecting the autocrine and paracrine regulation of endometrial cell proliferation, a topic still under study.
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PMID:Prostaglandins and growth factors in the endometrium. 269 20

Stimulation of washed human platelets by the pro-inflammatory polysaccharide carrageenan is accompanied by shape change, aggregation and release of granule contents and unaccompanied by thromboxane A2 synthesis. Carrageenan triggers platelet activation through a prostaglandin synthetase-independent mechanism. The phospholipase A2 (PLA2) inhibitor, p-bromophenacyl bromide suppresses platelet responses to carrageenan (Vargaftig et al, 1980) probably by mechanism(s) other than those which involve PLA2 activity. Exposure of platelets to carrageenan (2-25 micrograms/ml) induced inositol phosphate formation in a time- and concentration-dependent manner, the level of inositol phosphate formation correlating with the intensity of aggregation. Neomycin, an aminoglycoside antibiotic which inhibits the phospholipase C-mediated phosphatidylinositol 4,5-bisphosphate breakdown, suppressed both platelet activation and inositol phosphate formation. Inhibition was concentration-dependent with an IC50 value of about 180 microM. Platelet-activating factor (PAF) is not responsible for carrageenan-induced platelet activation and inositol phosphate formation, since exposure of platelets to carrageenan (25 micrograms/ml) in the presence of compound WEB 2086 (100 microM), a PAF antagonist, failed to inhibit carrageenan responses. However, compound Ro 19-3704, a structurally related antagonist of PAF reported to be also an inhibitor of phospholipases A2 and C, inhibited concentration-dependently (0.1-10 microM) aggregation and ATP release induced by carrageenan (25 micrograms/ml). These findings indicate that carrageenan activates human platelets through a phospholipase C-dependent mechanism and show that neomycin, at low concentrations, can be a selective inhibitor of phospholipase C-mediated PIP2-breakdown.
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PMID:Carrageenan-induced activation of human platelets is dependent on the phospholipase C pathway. 845 75

Incubation of rat renal mesangial cells with platelet-derived growth factor (PDGF) -AB or -BB led to a transient increase in prostaglandin G/H synthase-2 (PGHS-2) mRNA expression with a maximum after two hours. Expression of PGHS-1 mRNA remained unchanged during short term incubation, but was enhanced about twofold after 8 to 12 hours incubation with PDGF-AB or -BB. Enhanced PGHS activity was still observed after 24 hours. Nevertheless, PGE2 release from mesangial cells was not enhanced by PDGF, hinting to the availability of arachidonic acid as rate-limiting step. PDGF receptors are coupled to multiple signaling pathways, among them phospholipase C gamma PDGF-BB rapidly phoshorylated PLC gamma, while phosphorylation by PDGF-AB was barely detectable. The differential effect of PDGF-BB and PDGF-AB was also seen with respect to calcium signaling: PDGF-BB but not PDGF-AB induced release of Ca2+ from internal stores. Activation of PLC and the resulting transient release of Ca2+ were not considered to be essential for PGHS-2 mRNA induction as both PDGF isoforms were equally effective in mRNA induction. Both PDGF isoforms led to a Ca2+ influx resulting in a long lasting elevation of [Ca2+]i. Enhanced [Ca2+]i seemed to be related to PGHS-2 mRNA expression, because PDGF-induced PGHS-2 mRNA was significantly reduced under Ca2+ free conditions. Diacylglycerol, liberated by PLC, is an activator of protein kinase C (PKC). Down-regulation of PKC by overnight incubation with phorbol ester (0.1 microM) attenuated PGHS-2 mRNA induction by PDGF-AB and -BB. Involvement of PKC was substantiated by the PKC inhibitor H7, which interfered with PDGF-mediated PGHS-2 mRNA expression, while HA1004, a considerably specific inhibitor of protein kinases A and G, was without effect. Taken together, signaling pathways other than PLC gamma seem to be involved in activation of PKC and elevation of [Ca2+]i, which were shown to be essential elements of PDGF-mediated induction of PGHS-2 mRNA expression in mesangial cells.
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PMID:Regulation of platelet-derived growth factor isoform-mediated expression of prostaglandin G/H synthase in mesangial cells. 880 74

Signaling pathways responsible for serotonin (5-HT)-mediated induction of early response genes prostaglandin G/H synthase-2 (PGHS-2, cyclooxygenase-2) and egr-1 were investigated in rat mesangial cells. Gene induction by 5-HT was dependent on 5-HT2A receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family. Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C (PLC) and release of Ca2+ from internal stores, but this activation was not related to PGHS-2 mRNA expression. Similarly, PI-3 kinase was not involved in 5-HT signaling. Instead, inhibition of phosphatidylcholine-specific PLC interfered with PGHS-2 and egr-1 mRNA induction, suggesting this enzyme as a link between 5-HT2A receptors and protein kinase C, an essential part of 5-HT-mediated signaling. The MAP kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression. Increase of intracellular cAMP by forskolin or dibutyryl cAMP did not induce PGHS-2 or egr-1 mRNA expression by itself, but strongly inhibited 5-HT-mediated mRNA induction. PGHS-2 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA, suggesting involvement of Ca2+-dependent enzymes. In contrast, egr-1 mRNA expression was superinduced in the presence of EGTA. Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps. Activation of the Gq-coupled 5-HT2A receptor thus leads to the expression of the early response genes PGHS-2 and egr-1, using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells, respectively.
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PMID:Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5-HT2A receptors. 957 79