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)

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.
...
PMID:Prostaglandins and growth factors in the endometrium. 269 20

A family of genes encoding four distinct muscarinic receptors (designated m1-m4) has been cloned and stably expressed in A9 L cells. When the m1 and m3 receptors were stimulated with carbachol, there was a rapid rise of liberated arachidonic acid, inositol phosphates, and cAMP, while m2 and m4 receptor stimulation had no detectable stimulation of these second messengers. Pretreatment with phorbol 12-myristate 13-acetate (PMA) caused a marked acceleration and amplification of m1 and m3 receptor-mediated arachidonic acid release. In contrast, m1- and m3-mediated inositol phosphate formation was inhibited by the same PMA pretreatment. Arachidonic acid release was unaffected by manipulations of cAMP levels. Arachidonic acid production was inhibited by calcium-free medium and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8; an inhibitor of cytosolic calcium mobilization) yet was unaffected by verapamil, a calcium-channel blocker. These experiments show that arachidonic acid release induced by the m1 and m3 receptors is regulated independently of phospholipase C and cAMP accumulation. Carbachol stimulation of the m1 and m3 cAMP accumulation. Carbachol stimulation of the m1 and m3 receptors also markedly decreased mitogenesis as measured by thymidine incorporation. The m1 receptor-mediated inhibition of mitogenesis could be partially blocked by indomethacin, a cyclooxygenase inhibitor. The inhibition of mitogenesis could be mimicked by cAMP elevation.
...
PMID:Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned genes for muscarinic receptor subtypes stably expressed in A9 L cells. 284 72

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

Previous investigations in this laboratory have indicated that arachidonic acid stimulates a rapid, dose-dependent, and reversible increase in human placental lactogen (hPL) release which is not dependent on cyclooxygenase or lipoxygenase metabolism. To investigate further the mechanism by which arachidonic acid stimulates the release of hPL, the effects of arachidonic acid on phosphoinositide hydrolysis were examined in an enriched cell culture population of term human syncytiotrophoblast. Phosphoinositide hydrolysis was assayed by three methods: the release of 3H from perfused cells prelabeled with [3H]myoinositol, the measurement of inositol phosphate accumulation, and the distribution of radioactivity in phospholipids separated by two-dimensional thin layer chromatography after exposure of 32P-labeled placental cells to arachidonic acid. Arachidonic acid stimulated a concentration-dependent, rapid, and reversible increase in the release of both [3H]myoinositol and hPL from perfused placental cells. This effect was not inhibited by prior incubation of cells with indomethacin (20 microM). In contrast, palmitic acid and oleic acid stimulated phosphoinositide hydrolysis only at a high concentration (100 microM). Arachidonic acid also stimulated the rapid appearance of inositol monophosphate in placental cells. The effect of arachidonic acid was specific for hydrolysis of phosphoinositides and phosphatidylserine and did not involve other phospholipids. Since phosphoinositide hydrolysis is associated with hormone release in a variety of secretory systems, these results suggest that the stimulation of hPL release by arachidonic acid may be mediated, at least in part, by the activation of phospholipase C.
...
PMID:Arachidonic acid stimulates phosphoinositide hydrolysis and human placental lactogen release in an enriched fraction of placental cells. 300 98

Thrombin-induced changes in arachidonate content of platelet phospholipids were quantitated to establish the ultimate origins of this eicosanoid precursor. Fifteen seconds following thrombin addition (15 U/5 X 10(9) platelets), phosphatidylcholine lost 11.8 nmol of arachidonate and phosphatidylethanolamine lost 10.5 nmol. Arachidonate in phosphatidate, phosphatidylinositol, and phosphatidylinositol-4,5-bisphosphate combined decreased by 11.0 nmol. Increases in free and oxygenated arachidonate (41 nmol) exceeded decreases in inositides. Thus phospholipase A2 released at least twice as much arachidonate as phospholipase C-diglyceride lipase. Phosphatidylinositol-4-phosphate levels remained unchanged upon stimulation. Therefore, increases in phosphatidylinositol-4,5-bisphosphate indicated the minimum rate of phosphorylation of phosphatidylinositol to resynthesize phosphatidylinositol-4,5-bisphosphate, following stimulus-induced breakdown by phospholipase C. Phosphatidylinositol-4, 5-bisphosphate increased 1.4 nmol between 10 and 15 sec following thrombin, markedly less than phosphatidylinositol decreased (2.1 nmol). This could be due to phospholipase A2, in addition to phospholipase C, acting directly on phosphatidylinositol to a greater extent than estimated by accumulation of lysophosphatidylinositol, degraded rapidly by lysophospholipase. Thus, upon high-dose thrombin stimulation of human platelets inositide metabolism via phospholipase C directs initial formation of intracellular second messengers, and sequentially, or in parallel, arachidonate release by phospholipase A2 supplies the larger proportion of arachidonate for syntheses of eicosanoids involved in intercellular communication.
...
PMID:Stimulated platelets release equivalent amounts of arachidonate from phosphatidylcholine, phosphatidylethanolamine, and inositides. 302 86

Cannabinoids were found to augment phospholipase activities and modify lipid levels of mouse brain synaptosomes, myelin and mitochondria. Delta-1-tetra-hydrocannabinol (delta 1-THC) and several of its metabolites induced a dose-dependent (0.32-16 microM) stimulation of phospholipase A2 (PLA2) activity resulting in the increased release of free arachidonic acid from exogenous [1-14C]phosphatidylcholine (PC). The potencies of the cannabinoids in modulating PLA2 activity were approximately of the order: 7-OH-delta 1-THC greater than delta 1-THC greater than 7-oxo-delta 1-THC greater than delta 1-THC-7-oic acid = 6 alpha OH-delta 1-THC much greater than 6 beta-OH-delta 1-THC. The hydrolysis of phosphatidylinositol (PI) by synaptosomal phospholipase C (PLC) was enhanced significantly by delta 1-THC and promoted diacylglyceride levels by greater than 100 percent compared to control values. In contrast, arachidonate was the major product resulting from phospholipase activities of a 20,000 g pellet. Synaptosomal diacylglyceride lipase activity was inhibited by delta 1-THC. [1-14C]Arachidonic acid was readily incorporated into subcellular membrane phospholipids and after exposure to cannabinoids led to diminished phosphoglyceride levels and concomitant increases in released neutral lipid products. These data suggest that cannabinoids control phospholipid turnover and metabolism in mouse brain preparations by the activation of phospholipases and, through this mechanism, may exert some of their effects.
...
PMID:Effects of cannabinoids on the activities of mouse brain lipases. 302 47

The biochemical events initiated by mitogen in T lymphocytes are the subject of this paper. Following interaction of the mitogen with its receptors, a transmembrane 'trigger-type' signal is propagated which has both positive and negative correlates. The negative signal occurs with high mitogen concentrations and is associated with membrane freezing, microtubular aggregation, receptor capping, adenylate cyclase activation, and cellular cyclic AMP increases. The positive signal occurs with optimal mitogen concentrations and is associated with changes in membrane permeability and transport with influx of calcium and potassium ion and efflux of sodium, in transport processes for glucose, amino acids, and nucleosides, and in a collected series of early membrane lipid changes which can be considered essential for the positive signal. These lipid changes include the uptake of arachidonic acid and other fatty acids, choline, phosphate and other molecules, their incorporation into membrane phospholipids, particularly phosphatidylinositol (PI), and a turnover of PI with the production of inositol triphosphate, which can be related to calcium mobilization and diacylglycerol which activates a cytoplasmic protein kinase C. A key event associated with mitogen action is arachidonic acid release. Arachidonic acid may give rise to prostaglandins and thromboxanes as part of negative components of the signal through effects on the adenylate cyclase/cyclic AMP system. Arachidonic acid gives rise to eicosanoids like 5-, 11-, possibly 12- and 15-hydroxyperoxy and hydroxy eicosatetraenoic acids and leukotrienes B4 and C4. The activation of the 5-lipoxygenase, a critical calcium-dependent step, leads via the production of 5-HPETE and 5-HETE to the activation of membrane and soluble guanylate cyclase and the production of cyclic GMP. Cyclic GMP appears to be essential for mitogen activation and is associated with cyclic GMP-dependent protein kinase activation and the phosphorylation of a number of substrates. Calcium ion influx is clearly central to mitogen action. Calcium through its influx and mobilization from cellular stores is thought to contribute directly and indirectly through the action of calmodulin and protein kinase C to the activation of a number of enzymatic processes involved in the positive signal including phospholipase C, diglyceride kinase and lipase, 5-lipoxygenase, and guanylate cyclase. Cyclic GMP and calcium ion both participate in nuclear processes leading to RNA and protein synthesis. Interleukin 2 is associated with midcycle increases in cyclic GMP and entry into DNA synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Transduction of signals in the activation of T lymphocytes: relation to leukemia. 304 Mar 20

One or more phospholipases of the C and A2 types exist in rodent islets and may play a pivotal role in the cell signaling cascade culminating in exocytotic insulin release. Phospholipase C generates myo-inositol-1,4,5-trisphosphate, which mobilizes a "pool" of calcium in the endoplasmic reticulum and which may also secondarily facilitate calcium (Ca++) influx from the extracellular space to replenish that pool. Diacylglycerol is also generated by phospholipase C action and activates protein kinase C; it may thereby potentiate the cellular response to elevations in cytosolic free Ca++ concentration. Arachidonic acid may be released during the degradation of diacylglycerol and may also contribute to islet activation. Phospholipase C is activated by glucose, cholinergic agonists, and probably by Ca++ fluxes. Phospholipase A2 action generates arachidonic acid and lysophospholipids. Certain lysophospholipids mobilize cellular Ca++, at least in part from superficial, plasmalemmal stores. Native (unoxygenated) arachidonic acid also has the capability of mobilizing cellular Ca++ from membrane-bound stores; it may, in addition, activate protein kinase C, as suggested by recent indirect studies. The further metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase appears to provide positive and negative modulation, respectively, of stimulated insulin secretion. Many pieces of the puzzle remain, however, to be supplied. For example, it has not yet been unequivocally demonstrated that phospholipase A2 is activated by physiologic stimuli in intact islets. Furthermore, the absence of truly specific pharmacologic stimulators or inhibitors of these processes currently precludes precise delineation of the respective physiologic roles of each potential mediator in stimulus-secretion coupling. When such roles are elucidated, it can be asked whether the defects in insulin secretion in diabetes mellitus may be due in part to abnormalities in the turnover of beta-cell membrane phospholipids and the generation of intracellular lipid-derived signals.
...
PMID:Membrane phospholipid turnover as an intermediary step in insulin secretion. Putative roles of phospholipases in cell signaling. 305 98

The involvement of arachidonic acid and arachidonic acid metabolites in the control of oxytocin secretion by ovine corpus luteum was investigated, using slices of luteal tissue incubated in vitro. Oxytocin was secreted at steady rates by luteal slices, during 60-min incubations (315.0 +/- 45.3 pg/mg.h). The secretion of oxytocin was stimulated by arachidonic acid, phospholipase A2 (PLA2), and phospholipase C (PLC) in a dose-dependent manner. The highest doses of arachidonic acid, PLA2, and PLC used stimulated oxytocin secretion by 145.8 +/- 23.0% (P less than 0.01; n = 6), 331.5 +/- 42.4% (P less than 0.02; n = 4), and 955.5 +/- 278.6% (P less than 0.01; n = 4), respectively. Oxytocin secretion by luteal slices was not affected by either prostaglandin F2 alpha (PGF2 alpha) or PGE2 over a concentration range from 3-3000 nM. Furthermore, inhibitors of the cyclo-oxygenase pathway of arachidonic acid metabolism did not consistently affect arachidonic acid and PLA2-stimulated oxytocin secretion. Nordihydroguaiaretic acid, which inhibits 5-lipoxygenase, however, totally abolished arachidonic acid- and reduced PLA2-stimulated oxytocin secretion. The presence of CoCl2 in the incubation medium also significantly reduced basal and PLA2- and PLC-stimulated oxytocin secretion [P less than 0.05 (n = 5), P less than 0.05 (n = 5), and P less than 0.01 (n = 6), respectively]. We have shown that oxytocin secretion from slices of ovine corpus luteum incubated in vitro is stimulated by exogenous and endogenously released arachidonic acid. The data show that PGF2 alpha and PGE2 do not have a role in luteal oxytocin secretion in vitro and PG formation does not appear to be involved in the stimulation of oxytocin secretion elicited by arachidonic acid or PLA2. Arachidonic acid may have its effect via the lipoxygenase pathway.
...
PMID:Control of oxytocin secretion by ovine corpora lutea: effects of arachidonic acid, phospholipases, and prostaglandins. 312 41

The human monocyte cell line, U937, can be induced to terminally differentiate into macrophage-like cells when treated with gamma-interferon. However, if these cells were treated with gamma-interferon and esculetin, an inhibitor of the lipoxygenase pathway, or BW755C, an inhibitor of both the lipoxygenase and the cyclooxygenase pathways, a marked inhibition in cellular differentiation occurred. In contrast, inhibitors of only the cyclooxygenase pathway had no effect on differentiation. These studies suggest a role for lipoxygenase products of arachidonic acid in the differentiation of the human U937 cell line. Arachidonic acid utilized in the production of eicosanoids is derived from phospholipids by the action of phospholipase A2 and phospholipase C. When U937 cells were cultured in medium supplemented with gamma-interferon, there was a striking increase in the level of phosphatidylcholine and phosphatidylethanolamine-specific phospholipase A2 activities and phosphatidylinositol-specific phospholipase C activity as compared to control cells. More ever, although there was not a significant difference in the incorporation of labeled arachidonic acid or linoleic acid into the major phospholipids of differentiated U937 cells as compared to undifferentiated control cells, there was a marked increase in the relative amount of the labeled arachidonic acid released from the differentiated cells as lipoxygenase products compared to cyclooxygenase products. These data suggest that lipoxygenase products may be essential in the differentiation process of U937 cells and that enhanced phospholipase enzyme activities that occur during differentiation help explain how arachidonic acid becomes available to form lipoxygenase products.
...
PMID:The role of fatty acid metabolites in the differentiation of the human monocyte-like cell line U937. 313 4


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---