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)

PGE2 is a powerful modulator of uterine contractility, but there is uncertainty as to which receptor subtypes (EP1, EP2, EP3, or EP4), G proteins, and second messenger systems are activated by PGE2 in myometrium. Here we show that in cultured human myometrial cells, PGE2 (1-100 microM) activates phospholipase C (PLC) up to 500% over the control level and elevates intracellular calcium ([Ca2+]i) from the resting level of 60-90 nM up to 350 nM in a concentration-dependent manner. Stimulation by the receptor subtype-selective analogs GR63799X (EP3), sulprostone (EP3 > EP1), and misoprostol (EP3 > EP2 > EP1) indicates that these effects are transmitted through EP3 receptors. Both effects are resistant to pertussis toxin (PT). Lower concentrations of PGE2 (1-300 nM) increase [Ca2+]i via a PT-sensitive pathway, without PLC activation. This [Ca2+]i increase occurs after an inverse dose-related delay and is inhibited by the selective EP1 antagonist AH6809 and calcium channel blockers. By comparison, oxytocin stimulates PLC up to 1000% over the control level and elevates [Ca2+]i up to 800 nM in a concentration-dependent manner without any measurable delay; both effects are partly sensitive to PT. These data provide functional evidence for the presence of different stimulatory mechanisms for PGE2 in myometrium: 1) a low affinity receptor (probably EP3D) that activates PLC through a PT-insensitive pathway; and 2) a high affinity receptor (probably EP1), independent from PLC and involving a PT-sensitive G protein (G(i)?). Both pathways lead to elevation of [Ca2+]i.
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PMID:Prostaglandin E2 activates phospholipase C and elevates intracellular calcium in cultured myometrial cells: involvement of EP1 and EP3 receptor subtypes. 864 Dec 11

In rat ovarian granulosa cells the effects of GnRH are determined by the state of granulosa cell development with mainly inhibitory actions in immature cells and stimulatory actions in differentiated mature cells. These developmentally related effects of GnRH may arise from changes in either one or more of the signal transduction pathways activated by GnRH. The present study therefore measured downstream signalling events associated with the activation of the phospholipase C (PLC) signal transduction pathway in both mature and immature rat ovarian granulosa cells. Results showed that GnRH produced similar total inositol phosphate and intracellular calcium ([Ca2+]i) responses in both immature and mature granulosa cells. In contrast to the biphasic GnRH-induced [Ca2+]i response in pituitary gonadotropes, stimulation of the endogenously expressed GnRH receptor in both immature and mature granulosa cells produced a prompt monophasic rise in [Ca2+]i. This calcium transient was abolished by pretreating either cell type with a potent GnRH receptor antagonist or the PLC inhibitor U73122, demonstrating a GnRH receptor-specific activation of PLC. Similarly, pretreatment of cells with the [Ca2+]i antagonists thapsigargin or cyclopiazonic acid abolished the GnRH-induced calcium transient, whereas EGTA and nifedipine, a voltage-operated calcium channel (VOCC) antagonist, had no effect. These results suggest that in either immature or mature granulosa cells GnRH mobilises calcium from thapsigargin/cyclopiazonic acid-sensitive [Ca2+]i stores but does not involve the influx of extracellular calcium through VOCCs. We conclude that GnRH-induced stimulation of the PLC signal transduction pathway is independent of the stage of granulosa cell maturity and that alternative mechanisms account for the opposite effects of GnRH on gonadotrophin-induced steroidogenesis in mature and immature rat granulosa cells in vitro.
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PMID:GnRH-induced calcium mobilisation and inositol phosphate production in immature and mature rat ovarian granulosa cells. 869 Nov 3

We investigated the early effects (5-60 s) of progesterone (1 pM-0.1 microM) on cytosolic free calcium concentration ([Ca2+]i) and inositol 1,4,5-trisphosphate (InsP3) formation in nonluteinized and in vitro luteinized porcine granulosa cells (pGCs). Progesterone increased [Ca2+]i and InsP3 formation within 5 s in both cell types. Progesterone induced calcium mobilization from the endoplasmic reticulum via the activation of a phospholipase C linked to a pertussis-insensitive G-protein. This process was controlled by protein kinases C and A. In contrast, only nonluteinized pGCs showed a Ca2+ influx via dihydropyridine-insensitive calcium channel. In both cell types, the nuclear progesterone receptor antagonist RU-38486 did not inhibit the progesterone-induced increase in [Ca2+]i, progesterone immobilized on bovine serum albumin, which did not enter the cell, increased [Ca2+]i within 5 s and was a full agonist, but less potent than the free progesterone; pertussis toxin did not inhibit progesterone effect on InsP3. In conclusion, progesterone may interact with membrane unconventional receptors that belong to the class of membrane receptors coupled to a phospholipase C via a pertussis toxin-insensitive G-protein. The source of the Ca2+ for the progesterone-induced increase in [Ca2+]i also depends on the stage of cell luteinization.
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PMID:Progesterone triggers rapid transmembrane calcium influx and/or calcium mobilization from endoplasmic reticulum, via a pertussis-insensitive G-protein in granulosa cells in relation to luteinization process. 880 86

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

The fragment of beta-amyloid comprised of amino acids 25-35 induces a rapid, concentration-dependent increase in cytosolic free calcium levels in suspensions of PC12 neuronal cells. This action of beta-amyloid 25-35 is not altered by pretreatment with the calcium channel blockers nifedipine or cobalt, with the depleter of intracellular calcium stores cyclopiazonic acid, or with the phospholipase C inhibitor neomycin. However, the effects of beta-amyloid 25-35 on cytosolic free calcium are absent in calcium-free buffer and are blocked by the antioxidant lazaroid U-83836E and by vitamin E. beta-Amyloid 25-35 is also neurotoxic and produces a concentration-dependent reduction in the viability of PC12 cells in culture. The neurotoxic action of beta-amyloid is blocked by U-83836E and vitamin E but not by nifedipine or cobalt. These data indicate that both the disruption of calcium homeostasis and the reduction of cell viability produced by beta-amyloid in PC12 cells are mediated by free radical-based processes.
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PMID:Actions of neurotoxic beta-amyloid on calcium homeostasis and viability of PC12 cells are blocked by antioxidants but not by calcium channel antagonists. 885 23

Prostaglandin E2 (PGE2) is one of the most potent stimulators of bone formation in vivo. In these studies, we investigated the mechanism(s) underlying PGE2 effects on human bone formation by evaluating the effects of PGE2 on normal human bone cell (HBC) proliferation in vitro. Cell proliferation of normal HBCs was increased by PGE2 as measured by increased [3H]thymidine incorporation after 18 h and increased cell number after 48 h of treatment. The effect of PGE2 to stimulate cell proliferation was biphasic, with a maximum stimulation between 0.01 and 1.0 nM PGE2 in different experiments. At higher concentrations of PGE2 (0.1 microM), HBC proliferation was inhibited. Signal transduction for PGE2 has been reported to include both protein kinase A (PKA) and protein kinase C (PKC) pathways. In these studies, concentrations of PGE2 which stimulated cell proliferation did not increase cyclic adenosine monophosphate (cAMP) production. However, higher concentrations of PGE2 increased cAMP production (7- to 12-fold at 1-10 microM) and inhibited cell proliferation. Because stimulators of PKC, such as phorbol esters, have been reported to stimulate cell proliferation, the action of PKC inhibitors were tested. Both staurosporine and sangivamysin (PKC inhibitors) totally abrogated the effect of PGE2 to stimulate cell proliferation. Additional studies revealed that PGE2 increased 45Ca uptake in a dose-dependent manner with a peak response occurring between 1 and 10 nM PGE2 concentrations in different experiments. Furthermore, when the calcium channel blocker, verapamil, was added to HBC cultures treated with PGE2, the stimulation of 45Ca uptake and cell proliferation by PGE2 was completely blocked. These data suggest that PGE2 increases cell proliferation through activation of a verapamil-sensitive calcium channel. In conclusion, these data are consistent with a model in which stimulation of HBC proliferation by low doses of PGE2 is mediated by an enhancement of phospholipase C, which results in both an increase in PKC activity and an increase in intracellular calcium influx.
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PMID:Evaluation of signal transduction mechanisms for the mitogenic effects of prostaglandin E2 in normal human bone cells in vitro. 888 40

The methyl ester of pyruvic acid (methyl pyruvate) stimulated a dose-dependent increase in insulin secretion from isolated perifused rat islets. The threshold level for release was about 10 mM, and at 20 mM the addition of MP to perifused islets resulted in a large first phase of secretion followed by an insulin-secretory response that was sustained for at least 40 min. When compared to the effects of 20 mM glucose, peak first-phase release rates in response to 20 mM methyl pyruvate were comparable, but the second phase of release was only about 10-15% of that observed with an equimolar level of the hexose. The stimulatory effects of 20 mM methyl pyruvate on secretion were abolished by the K1+-ATP channel blocker diazoxide (200 microM) and by the calcium channel antagonist nitrendipine (500 nM). The glucokinase inhibitor mannoheptulose (20 mM) had no adverse effect on the secretory response to 20 mM methyl pyruvate, whereas 10 microM forskolin amplified the insulinotropic action of MP. Sodium pyruvate alone or in combination with 10 microM forskolin had no insulinotropic effect. In additional experiments islet phosphoinositide pools were labeled with myo-2-[3H]inositol, and the subsequent accumulation of labeled inositol phosphates was used to monitor the activation of phospholipase C. Methyl pyruvate stimulated a dose-dependent increase in inositol phosphate levels when measured after a 30-min incubation period with a maximal increase of about 300% at 20 mM methyl pyruvate. The increase in phosphoinositide hydrolysis caused by methyl pyruvate (20 mM) was, like insulin secretion, reduced by both diazoxide and nitrendipine but was immune to inhibition by mannoheptulose. Pyruvate (20 mM) had no effect on inositol phosphate accumulation. Prior short-term exposure to methyl pyruvate sensitized islets to subsequent stimulation with 15 mM glucose. Sodium pyruvate did not sensitize islets. These findings support the concept that the mitochondrial metabolism of nutrient molecules is an event sufficient to acutely augment insulin release from the beta cell, to increase phospholipase C-mediated phosphoinositide hydrolysis, and to induce time-dependent potentiation of insulin secretion.
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PMID:Influence of pyruvic acid methyl ester on rat pancreatic islets. Effects on insulin secretion, phosphoinositide hydrolysis, and sensitization of the beta cell. 901

The effects of phosphonofluoridic acid, methyl-5,8,11,14-eicosatetraenyl ester (MAFP), a phospholipase A2 inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), the calcium channel opener BAY K 8644, and the thromboxane A2 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 BAY K 8644 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure that were reproducible with respect to time. Infusion of MAFP into the perfused lobar artery at doses of 100 to 300 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II; however, the phospholipase A2 inhibitor did not alter vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. The combination of the higher dose of the phospholipase A2 inhibitor MAFP with the phospholipase C inhibitor U-73122 significantly affected vasoconstrictor responses to ANG II, NE, and 5-HT but not to BAY K 8644. In a separate series of animals, the effects of a lipoxygenase inhibitor, baicalein, were investigated. Infusion of baicalein into the perfused lobar artery at doses of 100 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II but not the vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. In a final series of experiments, the effects of a cyclooxygenase inhibitor, meclofenamate, were investigated, and intravenous injection of the meclofenamate at a dose of 2.5 mg/kg did not significantly affect vasoconstrictor responses to ANG II, 5-HT, BAY K 8644, NE, or U-46619. These data provide support for the hypothesis that pulmonary vasopressor responses to ANG II are mediated, in part, by the activation of phospholipase A2, phospholipase C, and the lipoxygenase pathway in the pulmonary vascular bed of the cat.
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PMID:Effects of phospholipase A2, 12-lipoxygenase, and cyclooxygenase inhibitors in the feline pulmonary bed. 914 27

Productive interaction between receptors and G proteins involves multiple intracellular receptor domains, but the role of individual receptor amino acids in directing the selection of specific signaling pathways has not yet been identified. Sequence alignment of several G protein-coupled receptors identified a highly conserved threonine residue in the i2 loop of the 5-hydroxytryptamine 1A (5-HT1A) receptor that is a putative protein kinase C phosphorylation consensus site and is located in a predicted amphipathic alpha-helical domain. To examine the role of this conserved threonine residue in 5-HT1A receptor coupling to Gi/Go proteins, this residue was mutated to alanine (T149A mutant). Wild-type and mutant 5-HT1A receptors were stably transfected into both Ltk- and GH4C1 cells to investigate receptor coupling to multiple signaling pathways. In both cell lines, the T149A mutant displayed similar agonist affinities as the wild-type receptor. In Ltk- cells, the T149A 5-HT1A receptor inhibited cAMP accumulation by 30% compared with wild-type (83%). A 2.6-fold increase in intracellular calcium (due to phospholipase C-mediated calcium mobilization) was observed for the wild-type receptor upon the addition of 100 nM 5-HT; whereas the T149A 5-HT1A receptor failed to mediate a calcium mobilization response at equivalent receptor levels to wild-type. When transfected in GH4C1 cells, the T149A receptor mutant fully inhibited basal cAMP and partially inhibited Gs-stimulated cAMP accumulation compared with wild-type receptor (57 +/- 14% versus 86 +/- 2%). In contrast, the T149A 5-HT1A receptor mutant failed to block the influx of calcium induced by calcium channel agonist (+/-)-Bay K8644, whereas the wild-type 5-HT1A receptor inhibited the calcium influx by 40%. Thus, the Thr149 residue is directly involved in G protein coupling to calcium mobilization (mediated by betagamma subunits of Gi2) and to inhibition of calcium channel activation (mediated by betagamma subunits of Go) but plays a minor role in coupling to alpha1-mediated inhibition of cAMP accumulation. The conserved i2 loop threonine may serve as a G protein contact site to direct the signaling specificity of multiple receptors.
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PMID:A conserved threonine residue in the second intracellular loop of the 5-hydroxytryptamine 1A receptor directs signaling specificity. 922 26

Silica is a well-known occupational fibrogenic agent and its primary target cell is alveolar macrophage. Particle-stimulated macrophages are believed to release various mediator which can regulate the inflammation as well as pulmonary fibrosis. Even though oxygen radicals play the major role among these mediators, the mechanisms concerning the stimulation of alveolar macrophages are not clear yet. The present study was carried out to investigate the signal transduction pathway on oxygen radical generation in silica-stimulated alveolar macrophages. Silica induced oxygen radical generation in a dose-response pattern. Extracellular calcium depletion, calcium channel blockers, and calcium release blocker decreased the effect of silica on oxygen radical generation. Silica increased intracellular calcium through the influx of calcium through the calcium channel and the calcium release from the intracellular calcium store. To know the role of protein kinase C (PKC), phospholipase C (PLC), and protein tyrosine kinase (PTK) in silica-induced oxygen radical generation, we pretreated alveolar macrophages with inhibitors of these enzymes. Inhibitors of PKC (sphingosine and staurosporine), PLC (neomycin and U-73122), and PTK (genistein and erbstatin) suppressed the silica-induced oxygen radical generation. Silica increased the PLC activity at the concentration of 5 mg/ml. The inhibitors of PTK and PLC suppressed the action of silica on the PLC activity. From these results, we suggest that silica induces oxygen radical generation through PTK, PLC, and PKC in alveolar macrophages.
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PMID:Silica-induced oxygen radical generation in alveolar macrophage. 924 22


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