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)

Adenosine-5'trisphosphate (ATP) is stored and co-released with various neurotransmitters but it may also act as a fast excitatory neurotransmitter trough the activation of purinoreceptor(s). In this study the effect of ATP on phospholipase C (PLC) degrading labelled PtdIns(4,5)P2 and PtdIns in brain cortex slices, brain homogenate and subcellular fractions was investigated. It was found that ATP added into brain slices activated significantly and specifically PtdIns(4,5)P2 degradation and this process was inhibited by theophylline. Moreover, ATP maintained a higher level of inositol(1,4,5)P3 radioactivity in total water-soluble inositol metabolites. However, ATP added directly for the assay of PLC into brain homogenate or subcellular fractions inhibits phosphoinositide degradation in a receptor-independent manner and suppresses conversion of Ins(1,4,5)P3 into Ins(1,4)P2. Our results indicate that ATP acting extracellularly through a purinergic receptor(s) activates PtdIns(4,5)P2 degradation and release of Ins(1,4,5)P3. ATP acting directly on PLC inhibits in a receptor-independent manner phosphoinositide degradation, and protects against liberation of lipid-derived second messengers.
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PMID:ATP a potent regulator of inositol phospholipids-phospholipase C and lipid mediators in brain cortex. 876 2

The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein alpha-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter receptor agonists was measured in membrane preparations from both groups. Phospholipase C-beta activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans-1-aminocyclopentyl-1, 3-dicarboxylic acid (ACPD, a glutamatergic metabotropic receptor agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic receptor agonist) in the presence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of G alpha s and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
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PMID:Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. 881 80

Extracellular ATP has been reported to exert mitogenic and contractile effects on cultured renal mesangial cells (MCs). Since it is possible that these actions involve changes in the cAMP second messenger system, we examined the effect of extracellular nucleotides on the accumulation of cAMP in rat MCs. ATP, UTP and adenosine 5'-0-(3-thio)triphosphate (ATP gamma S) (100 microM) had no significant effects on baseline cAMP levels, but inhibited forskolin-stimulated accumulation of cAMP by 21-75% in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Maximal inhibitory effects were observed at 100 microM of ATP gamma S with a threshold dose of 1 microM. ATP gamma S, ATP and UTP were the most potent inhibitors indicating stimulation of the P2u receptor. The P2x agonists adenosine 5'-(alpha, beta-methylene) triphosphate and adenosine 5'-(beta, gamma-methylene) triphosphate, and the P2y agonist 2-methylthio-ATP did not affect cAMP accumulation. Treatment with the P2 receptor antagonist suramin (200 microM) reduced the inhibition by 58%. The inhibitory effects of the nucleotides were significantly attenuated by preincubation with pertussis toxin (10-100 ng/ml). Inhibition of phospholipase C and protein kinase C did not prevent the inhibitory effect of the nucleotides. Inhibitors of forskolin-stimulated cAMP accumulation had different effects on DNA synthesis in cultured MCs as measured by 3H-thymidine uptake at 48 h: ATP, ATP gamma S and the inhibitor of adenylyl cyclase, SQ 22536, stimulated DNA synthesis in MCs, while UTP showed no significant mitogenic effect. Agents which increased baseline levels of intracellular cAMP (forskolin, IBMX, dibutyryl-cAMP) significantly diminished DNA synthesis in MCs. The results indicate that the P2u-purinergic receptor mediates inhibition of forskolin-induced cAMP accumulation which is likely due to inhibition of adenylyl cyclase. This effect appears to be partially mediated by PTX-sensitive G proteins. While the increase in cAMP accumulation is anti-mitogenic, inhibition of cAMP accumulation by P2u receptors is not correlated with MC growth control. Thus, additional mechanisms other than inhibition of cAMP accumulation by P2u receptors are likely to be involved in the mitogenesis of extracellular ATP.
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PMID:P2U-purinergic receptor activation mediates inhibition of cAMP accumulation in cultured renal mesangial cells. 886 79

Lysophosphatidic acid (LPA) functions as an extracellular lipid mediator stimulating phospholipase C and affecting the structure of the cytoskeleton in several cell types. In rat glioma C6 cells, LPA mobilizes calcium from intracellular calcium stores and reverts morphological changes induced by elevated cytosolic cAMP-concentrations. Here we show that LPA-stimulation of C6 cells loaded with the calcium-sensitive fluorescent dye indo-1 results in calcium release from a subset of intracellular calcium stores that are not sensitive to the tumor promoter thapsigargin and do not overlap with calcium stores depleted during purinergic receptor stimulation with ATP. Furthermore, depletion of LPA-sensitive calcium stores does not induce capacitative calcium entry from the extracellular space into the cytosol to the same extent as ATP. These results indicate that inositol phosphate signaling induced by LPA or ATP may differ in kinetics or in spatial organisation within the cell. This may represent a possible explanation for the previous observation that only LPA, but not other calcium-mobilizing agonists, reverts cAMP-induced changes in the cytoskeletal organization in C6 cells.
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PMID:Lysophosphatidic acid depletes intracellular calcium stores different from those mediating capacitative calcium entry in C6 rat glioma cells. 898 69

Extracellular ATP, and to a lesser extent adenosine, an ATP metabolite, stimulated cell proliferation in osteoblast-like cells (MC3T3-E1). ATP increased cytosolic Ca2+ due to Ca2+ mobilization from intracellular storage in the same concentration range of the nucleotide as that effective for DNA synthesis, suggesting the mediation of the phospholipase C/Ca2+ system in the mitogenic action. Since adenosine induced no Ca2+ mobilization, P2-purinergic receptor appears to be associated with ATP actions. The growth-promoting effect of ATP was not inhibited by H7, a protein kinase C inhibitor, and indomethacin, a cyclooxygenase inhibitor, indicating no involvement of activation of protein kinase C and production of prostaglandins in ATP-induced mitogenic signals. Either ATP or adenosine remarkably and synergistically potentiated platelet derived growth factor-induced DNA synthesis. These findings suggest that extracellular ATP and adenosine may play a physiological role in the regulation of bone formation.
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PMID:ATP and adenosine act as a mitogen for osteoblast-like cells (MC3T3-E1). 899 80

Intracellular Ca2+ is an important second messenger. In the placenta, regulation of intracellular Ca2+ concentration ([Ca2+]i) by extracellular factors has received relatively little attention. Cultured human placental trophoblasts were treated with a series of potential Ca(2+)-mobilizing ligands. After 3 days in culture, there was an increase in [Ca2+]i in response to angiotensin, endothelin, transforming growth factor-alpha, and ATP in approximately 8, 54, 17, and 100% of the cells, respectively. The response to ATP was dose dependent. At low ATP concentrations (1-10 microM), the response to repeat ATP application remained unchanged, whereas at 100 microM, response to repeat stimulation resulted in lower peak value. The order of potency for the ATP derivatives was ATP = UTP > benzoylbenzoic-ATP > ATP gamma S > ADP beta S > ADP > alpha,beta-MeATP > AMP. This suggests action via the P2u purinergic receptor. Removal of extracellular Ca2+ decreased the ATP-induced Ca2+ response by 45%; this indicates that a substantial portion of the increase in [Ca2+]i was due to influx from extracellular space. Finally, ATP rapidly induced inositol 1,4,5-trisphosphate formation in cultured trophoblasts. Therefore, ATP-induced changes in Ca2+ flux may be due in part to activation of phosphoinositide-specific phospholipase C. In summary, ATP is a potent calciotropic ligand in human placental trophoblasts, acting through the P2u receptor. The effect of ATP on [Ca2+]i may prove to be involved in the modulation of various trophoblast functions, including hormone secretion and active transport of nutrients.
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PMID:Ca2+ flux in human placental trophoblasts. 922 4

The signal transduction involved in the purinergic stimuli-induced activation of protein kinase C (PKC) in CHO-K1 cells was investigated. Purinergic stimuli such as adenosine triphosphate and uridine triphosphate induced a transient translocation of PKC epsilon, gamma, and delta from the cytoplasm to the plasma membrane. These translocations were blocked by an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), but not by an inhibitor of phosphatidylcholine-specific PLC. A diacylglycerol (DAG) analogue also induced reversible translocations of PKC gamma, epsilon, and delta from the cytoplasm to the plasma membrane, while the calcium ionophore A23187 caused a similar translocation of only the gamma subtype. These results confirm that the hydrolysis of phosphatidylinositol-2-phosphate by PLC and the subsequent generation of DAG and increase in Ca(2+ )are involved in the purinergic stimuli-induced translocation of PKC. A DAG antagonist, 1-o-hexadecyl-2-o-acetyl-glycerol, blocked the DAG analogue-induced translocations of all PKC subtypes tested but failed to inhibit the purinergic stimuli-induced translocations of PKC epsilon and gamma. The DAG antagonist could not block the ATP- and UTP-induced translocation of PKC epsilon even in the absence of extracellular Ca(2+). Co-application of the DAG antagonist and a phospholipase A(2) (PLA(2)) inhibitor such as aristolochic acid, arachidonyltrifluoromethyl ketone, or bromoenol lactone inhibited the purinergic receptor-mediated translocation of PKC epsilon although each PLA(2) inhibitor alone did not block the translocation. In contrast to the epsilon subtype, ATP-induced translocation of PKC gamma was observed in the presence of both the PLA(2) inhibitor and the DAG antagonist. However, it is noteworthy that re-translocation of PKC gamma was hastened by the PLA(2) inhibitor. Furthermore products of PLA(2), such as lysophospholipids and fatty acids, induced the translocation of PKC gamma and epsilon in a dose dependent manner, but not delta. These results indicate that, in addition to PLC and DAG, PLA(2) and its products are involved in the purinergic stimuli-induced translocation of PKC epsilon and gamma in CHO-K1 cells. Each subtype of PKC in CHO-K1 cell is individually activated in response to a purinergic stimulation.
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PMID:Phospholipase A(2) and its products are involved in the purinergic receptor-mediated translocation of protein kinase C in CHO-K1 cells. 1072 17

We have used the patch-clamp technique to study the effects of changing extracellular ATP concentration on the activity of the small-conductance potassium channel (SK) on the apical membrane of the mouse cortical collecting duct. In cell-attached patches, the channel conductance and kinetics were similar to its rat homologue. Addition of ATP to the bathing solution of split-open single cortical collecting ducts inhibited SK activity. The inhibition of the channel by ATP was reversible, concentration dependent (K(i) = 64 microM), and could be completely prevented by pretreatment with suramin, a specific purinergic receptor (P(2)) blocker. Ranking of the inhibitory potency of several nucleotides showed strong inhibition by ATP, UTP, and ATP-gamma-S, whereas alpha, beta-Me ATP, and 2-Mes ATP failed to affect channel activity. This nucleotide sensitivity is consistent with P(2)Y(2) purinergic receptors mediating the inhibition of SK by ATP. Single channel analysis further demonstrated that the inhibitory effects of ATP could be elicited through activation of apical receptors. Moreover, the observation that fluoride mimicked the inhibitory action of ATP suggests the activation of G proteins during purinergic receptor stimulation. Channel inhibition by ATP was not affected by blocking phospholipase C and protein kinase C. However, whereas cAMP prevented channel blocking by ATP, blocking protein kinase A failed to abolish the inhibitory effects of ATP. The reduction of K channel activity by ATP could be prevented by okadaic acid, an inhibitor of protein phosphatases, and KT5823, an agent that blocks protein kinase G. Moreover, the effect of ATP was mimicked by cGMP and blocked by L-NAME (N(G)-nitro-l-arginine methyl ester). We conclude that the inhibitory effect of ATP on the apical K channel is mediated by stimulation of P(2)Y(2) receptors and results from increasing dephosphorylation by enhancing PKG-sensitive phosphatase activity.
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PMID:Extracellular ATP inhibits the small-conductance K channel on the apical membrane of the cortical collecting duct from mouse kidney. 1091 72

Exocrine secretions proceed in two phases which can be studied individually in submandibular glands. We have investigated the response to neuropeptides and purinergic agonists of rat submandibular glands. Pituitary Adenylate Cyclase Activating Peptide (PACAP), an analog of VIP increased the intracellular concentration of cyclic AMP in acinar cells. PACAP also stimulated the activity of the Na(+)-K(+)-2Cl(-)-cotransporter. Extracellular ATP increased the [Ca2+]i in ductal cells. Two distinct receptors were involved in this response. A metabotropic purinergic receptor of the P2Y1 type raised the cellular concentration of IP3 after activating a phospholipase C. The second component of the purinergic response involved an ionotropic P2X7 receptor. After binding an agonist, this receptor formed a non-specific cation channel permeant to calcium and manganese, highly sensitive to inhibition by nickel. Two phospholipases A2 were activated following the occupancy of this receptor. The calcium-independent enzyme triggered kallikrein secretion in response to extracellular ATP. In conclusion, neuropeptides and purinergic agonists activate the acinar and ductal phases of the salivary secretion and are therefore promising candidates for the development of new sialagogues for therapeutic use.
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PMID:[Value of new agonists of the acinar and ductal phases of exocrine secretions]. 1099 84

Pituitary folliculo-stellate cells (FSCs) are glia-like cells in the anterior pituitary and are believed to modulate the activity of the pituitary endocrine cells. However, little is known what regulates the activity of FSCs. We hypothesized that ATP could act on FSCs, because ATP is coreleased with pituitary hormones from endocrine cells. To test this possibility, we examined the effect of ATP by measuring intracellular Ca2+ concentration [Ca2+]i of FSCs in primary culture. Both ATP and UTP increased the [Ca2+]i in a concentration-dependent manner in a range between 0.1 microM and 10 microM. The response was completely suppressed by thapsigargin, an inhibitior of endoplasmic reticulum Ca2+-ATPase, and was significantly suppressed by U-73122, an inhibitor of phospholipase C. The response was also suppressed by caffeine, a blocker of IP3 receptor, whereas that was not suppressed by ryanodine, an antagonist of ryanodine receptor. These results indicate that ATP increases [Ca2+]i of FSCs by activating phospholipase C via P2Y purinergic receptor and suggest that ATP would be one of paracrine factors to FSCs in the anterior pituitary.
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PMID:Purinergic regulation of intracellular Ca2+ concentration of rat pituitary folliculo-stellate cells in primary culture. 1126 26


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