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)

The role of extracellular nucleotides in intracellular signalling and neurosecretion was assessed in PC12 cells. Activation of phospholipase C and increased [Ca2+]i were mediated by purinoceptors with an agonist potency profile, ATP approximately UTP > 2-methylthioadenosine triphosphate (2-MeSATP), typical of P2U. ATP also evoked a rapid acidification followed by a more gradual alkalinization (measured with 2',7'-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF)), while UTP induced only a gradual alkalinization. The amiloride analogue 5-(N-ethyl-N-isopropyl)amiloride (EIPA) attenuated the alkalinization phase suggesting activation of the Na+/H+ exchanger by ATP and UTP. Using bisoxonol and [3H]tetraphenylphosphonium ([3H]TPP+) as potential-sensitive probes, we showed that while ATP rapidly depolarized PC12 cells in an Na(+)-dependent manner, UTP evoked a much reduced and delayed response. The potency profile (ATP approximately 2-MeSATP approximately adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) >> UTP, alpha, beta-methyleneATP) suggested involvement of a receptor subtype distinct from P2U. Secretion of endogenous dopamine was also assessed. Those nucleotides that induced depolarization (ATP, 2-MeSATP, ATP gamma S) were also the most potent secretagogues. UTP was ineffective. Our results suggest that ATP stimulates distinct purinoceptor subtypes and induces neurosecretion through the activation of multiple signalling pathways.
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PMID:Purine and pyrimidine nucleotides activate distinct signalling pathways in PC12 cells. 750 Mar 77

1. Purinoceptor responses were analyzed in B10 cells, a clonal population of rat brain capillary endothelial cells. 2. B10 cells lack P2U receptors as evidenced by the lack of UTP responses and the failure to amplify P2U-related sequences by polymerase chain reaction. 3. B10 cells responded to adenine nucleotides by large increases in [Ca2+]i. Half maximum effective concentrations were 2-methylthio-ATP: 180 nM > 2-chloro-ATP: 310 nM = ADP: 330 nM > adenosine 5'-O-(3-thiotrisphosphate): 2.3 microM = ATP: 2.7 microM. The maximum response to ATP was only 55% of that to ADP while that to ATP derivatives was 75%. 4. The actions of adenine nucleotides were not associated with a measurable activation of phospholipase C. 5. Cross desensitizations of the actions of ADP and ATP were observed. 6. In additivity experiments, ADP superposed its action on top of that of ATP and ATP partially inhibited the action of ADP. 7. It is concluded that ATP acts as a partial agonist of the P2Y-like receptor of brain capillary endothelial cells.
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PMID:ATP, a partial agonist of atypical P2Y purinoceptors in rat brain microvascular endothelial cells. 758 45

The cDNA encoding a novel P2 receptor was isolated from rat aortic smooth muscle cell library and functionally characterized. The cloned P2 receptor exhibits structural features characteristic of the G protein-coupled receptor family and shows 44 and 38% amino acid identity with previously cloned rat P2U and chicken P2Y receptors, respectively. The cloned P2 receptor is functionally coupled to phospholipase C but not to adenylate cyclase in C6 rat glioma cells transfected with the cloned P2 expression vector. The rank order of agonist potency as judged by intracellular Ca2+ mobilization responses is UTP > ADP = 2-methylthioATP > ADP beta S > ATP = ATP gamma S, which is not compatible with any of the previously characterized P2 receptor subtypes. The nonselective P2 antagonists, suramin and reactive blue-2, inhibit nucleotide-induced phospholipase C activation in cells expressing the cloned P2 receptor. The cloned P2 receptor mRNA is abundantly expressed in various rat tissues including lung, stomach, intestine, spleen, mesentery, heart, and, most prominently, aorta. The results indicate that the novel metabotropic P2 receptor has pharmacological characteristics distinct from any of P2 receptor subtypes thus far identified and suggest the existence of a novel regulatory system by extracellular nucleotides of potential significance.
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PMID:Molecular cloning and functional analysis of a novel P2 nucleotide receptor. 759 19

Extracellular sphingosylphosphorylcholine (SPC) and galactosylsphingosine (psychosine) induced Ca2+ mobilization in a dose-dependent manner in HL60 leukemia cells. The rapid and transient increase in intracellular Ca2+ concentration ([Ca2+]i) elicited by SPC and psychosine at concentrations lower than 30 microM was inhibited by treatment of the cells with pertussis toxin (PTX) and U73122, a phospholipase C inhibitor, as was the case for UTP, a P2-purinergic agonist. The increase in [Ca2+]i induced by these lysosphingolipids was associated with inositol phosphate production, which was also sensitive to PTX and U73122. The inositol phosphate response is not secondary to the increase in [Ca2+]i as evidenced by the observation that thapsigargin and ionomycin, Ca2+ mobilizing agents, never induced inositol phosphate production and, unlike lysosphingolipids, the [Ca2+]i rise by these agents was totally insensitive to PTX and U73122. When HL60 cells were differentiated into neutrophil-like cells by dibutyryl cyclic AMP, inositol phosphate and Ca2+ responses to AlF4- were enhanced, probably reflecting an increase in the amount of Gi2 and Gi3 compared with undifferentiated cells. In the neutrophil-like cells, however, the responses to SPC and psychosine were markedly attenuated. This may exclude the possibility that the lysosphingolipids activate rather directly PTX-sensitive GTP-binding proteins or the phospholipase C itself. Other lysosphingolipids including glucosylsphingosine (glucopsychosine) and sphingosylgalactosyl sulfate (lysosulfatides) at 30 microM or lower concentrations also showed PTX- and U73122-sensitive Ca2+ mobilization and inositol phosphate response in a way similar to SPC and psychosine. However, platelet-activating factor and lysoglycerophospholipids such as lysophosphatidylcholine and lysophosphatidic acid were less effective than these lysosphingolipids in the induction of Ca2+ mobilization. Taken together, the results indicate that a group of lysosphingolipids at appropriate doses induces Ca2+ mobilization through inositol phosphate production by phospholipase C activation. The lysosphingolipids-induced enzyme activation may be mediated by PTX-sensitive GTP-binding protein-coupled receptors, which may be different from previously identified platelet-activating factor receptor or lysophosphatidic acid receptor.
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PMID:Pertussis toxin inhibits phospholipase C activation and Ca2+ mobilization by sphingosylphosphorylcholine and galactosylsphingosine in HL60 leukemia cells. Implications of GTP-binding protein-coupled receptors for lysosphingolipids. 759 44

1. The inhibitory effects of the putative phospholipase C beta inhibitor, U-73122, on ligand-induced and thapsigargin-induced [Ca2+]i transients were investigated in mouse fibroblast cells (the L line). 2. Ca2+ release from intracellular stores was stimulated either by ATP (and also by UTP or ADP) working through the activation of a P2U receptor, or by lysophosphatidic acid, which elicited a more pronounced response. 3. U-73122 inhibited the Ca2+ mobilization produced by all the agonists in a dose-dependent manner, consistent with a mode of action involving phospholipase C inhibition. 4. In addition, however, U-73122 slowed the kinetics of intracellular Ca2+ release induced by the Ca(2+)-ATPase inhibitor, thapsigargin, and reduced the influx of Ca2+ across the plasma membrane, following stimulation of store-dependent influx by the latter. 5. We conclude that U-73122 has multiple sites of action, all of which can lead to a change in Ca2+ homeostasis. Thus, particular caution is recommended when employing this agent and when interpreting the results obtained.
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PMID:Calcium homeostasis in mouse fibroblast cells: affected by U-73122, a putative phospholipase C beta blocker, via multiple mechanisms. 764 65

Extracellular ATP activates two distinct types of P2 purinoreceptor-mediated signaling pathways in macrophages, 1) the rapid formation of nonselective pores/channels in the plasma membrane and 2) a guanine nucleotide-binding protein-dependent stimulation of phosphotidylinositol-specific phospholipase C, with subsequent mobilization of intracellular Ca2+. Several studies have suggested that the pore-forming, or P2z, purinoreceptor may be involved in the cytolytic effects of ATP on macrophages and other cell types. We have identified 3'-O-(4-benzoyl)benzoyl-ATP (BzATP) and UTP as selective agonists for the P2z purinoreceptor and Ca(2+)-mobilizing nucleotide receptor, respectively, in BAC1.2F5 macrophages. In this paper we demonstrate that BzATP and ATP (but not UTP) activate membrane depolarization in BAC1.2F5 cells and also stimulate appropriate electrophysiological responses, consistent with the expression of the P2z purinoreceptor, in Xenopus oocytes injected with poly(A)+ RNA derived from BAC1.2F5 cells. Micromolar concentrations of BzATP or millimolar concentrations of ATP induced a sustained increase in the membrane holding current in these voltage-clamped oocytes. This response was significantly potentiated in the absence of extracellular divalent cations, consistent with the specificity of the P2z purinoreceptor for tetrabasic nucleotides. The sustained currents induced by BzATP or ATP were distinct from the transient and/or oscillating increases in Ca(2+)-dependent Cl- currents that were stimulated by UTP but not BzATP. UTP-stimulated transient currents and nucleotide-dependent increases in aequorin luminescence in poly(A)+ RNA-injected oocytes were independent of extracellular Ca2+ and were correlated with the mobilization of intracellular Ca2+ stores. Sucrose fractionation of the poly(A)+ RNA from BAC1.2F5 cells resulted in the enrichment of mRNA species encoding the components of the P2z purinoreceptor, as well as the Ca(2+)-mobilizing nucleotide receptor, in fractions containing 2.5-4.0-kilobase species.
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PMID:Expression of the pore-forming P2Z purinoreceptor in Xenopus oocytes injected with poly(A)+ RNA from murine macrophages. 768 70

In neuroblastoma x glioma hybrid NG108-15 cells, ATP induced a concentration-dependent increase in the intracellular Ca2+ concentration ([Ca2+]i), accompanied by inositol phosphate formation. Under the same conditions, we found a marked increase in cAMP levels produced by ATP at concentrations similar to those required to increase [Ca2+]i. The Ca2+ ionophore A23187 or bradykinin, which evoked inositol phosphate formation and increases in [Ca2+]i, did not increase, and instead slightly decreased, cAMP content, indicating that ATP-induced cAMP accumulation was not due to activation of Ca(2+)-sensitive adenylyl cyclase. The effect of ATP on cAMP production was not dependent on generation of adenosine caused by ATP hydrolysis. Among several P2 purinoceptor agonists, adenosine-5'-O-(3-thio)triphosphate, 5'-adenylylimidodiphosphate, and adenosine-5'-O-(2-thio)diphosphate evoked both cAMP accumulation and Ca2+ mobilization. In contrast, beta,gamma-methylene-ATP selectively elicited cAMP accumulation, whereas 2-methylthio-ATP and UTP induced only Ca2+ mobilization, without affecting cAMP levels. The potent P2x purinoceptor agonist alpha,beta-methylene-ATP did not induce cAMP accumulation or Ca2+ mobilization. The cAMP accumulation induced by ATP was not affected by the P2 receptor antagonist suramin but was inhibited by P1 receptor antagonists such as 8-(p-sulfophenyl)theophylline, 3-isobutyl-1-methylxanthine, and xanthine amine congener. However, the ATP-induced increase in [Ca2+]i was not affected by suramin or xanthine amine congener. Taken together, these results indicate that ATP activates two distinct purinoceptors that are coupled to different signal transduction systems, one being adenylyl cyclase and the other phospholipase C, in NG108-15 cells. Furthermore, pharmacological profiles of the adenylyl cyclase-coupled receptor were quite different from those of any known purinoceptor subtypes, especially in the unusual sensitivity of the receptor to P1 and P2 receptor agonists and antagonists. It is therefore suggested that ATP-induced cAMP accumulation may be mediated by a novel subtype of purinoceptor in NG108-15 cells.
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PMID:Extracellular ATP stimulates adenylyl cyclase and phospholipase C through distinct purinoceptors in NG108-15 cells. 772 48

Extracellular nucleotides are potent Ca2+ mobilizing agents. A variety of receptors for extracellular ATP are recognised. Some are involved in fast neuronal transmission and operate as ligand-gated ion channels. Others are involved in the paracrine or autocrine modulation of cell function. Many receptors of this type are coupled to phosphoinositide-specific phospholipase C and, in some cases, other phospholipases. One of these receptors (P2z), however, also appears to operate, at least in part, as a ligand-gated ion channel. Pharmacological data suggest that one nucleotide receptor subtype (currently designated P2U) responds selectively to either a purine nucleotide, ATP, or a pyrimidine nucleotide, UTP. According to an alternative view, ATP and UTP recognise distinct receptors. Because of the diversity of receptors for extracellular nucleotides this may be the case in some cells. Nevertheless, a G-protein coupled receptor that confers both ATP and UTP sensitivity has been cloned, expressed in cultured cell lines and sequenced. This receptor appears to have two ligand binding domains that may partially overlap. The nature of this overlap is discussed and a simple model presented. Activation of the receptor protein via one or other ligand binding domain may underlie some of the more subtle differences between the effects of ATP and UTP.
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PMID:Review: Ca(2+)-mobilizing receptors for ATP and UTP. 773 60

Activation of adenosine A1-, bradykinin- or P2U-receptors on DDT1 MF-2 smooth muscle cells all increased the formation of inositol 1,4,5-trisphosphate and the mobilization of intracellular calcium. All three types of agents could increase [Ca2+]i in the same cell. Activation of the P2U receptor with ATP or UTP produced larger responses than activation of bradykinin- and adenosine A1-receptors, with bradykinin and N6-cyclopentyladenosine. When agonist-stimulated levels of diacylglycerol were determined, all agonists caused biphasic changes of similar magnitudes. If anything, ATP and UTP tended to give larger increases in the second phase of stimulation. Phospholipase D, measured as the formation of phosphatidylethanol in cells labeled with [3H]palmitic acid and activated in the presence of ethanol, was activated similarly as phospholipase C, i.e. ATP or UTP caused the largest increase in phosphatidylethanol formation, followed by N6-cyclopentyladenosine and bradykinin which caused weaker responses. Activation of PLD by P2U receptors was pertussis toxin insensitive. The activation of PLD by the agonists was only weakly affected by a PKC inhibitor, Ro 31-7549 (3-[1-(3-aminopropanyl)-3- indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione). In contrast, ATP or UTP did not activate protein kinase C, determined in a permeabilized cell assay using two specific protein kinase C substrates, whereas N6-cyclopentyladenosine and bradykinin caused a substantial activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of phospholipase C and phospholipase D by stimulation of adenosine A1, bradykinin or P2U receptors does not correlate well with protein kinase C activation. 777 Jan 1

The P2U purinoceptor mediated effect on cellular cAMP was investigated in DDT1 MF-2 smooth muscle cells. Stimulation of these receptors by ATP or UTP caused a pronounced decrease of about 50% in cellular cAMP levels in forskolin or isoprenaline pretreated cells. This action of the nucleotides was concentration dependent with an IC50 of 9.4 +/- 0.2 microM and 29.0 +/- 0.5 microM for UTP and ATP, respectively and was inhibited by the P2-purinoceptor antagonist suramin. The cAMP level appeared to be modified by intracellular Ca2+, represented by an initial decline in cAMP. Neither inactivation of protein kinase C by staurosporine nor elevated cytoplasmic Ca2+ concentrations interfered with the sustained decrease in cAMP levels induced by ATP or UTP, showing that this effect is not mediated via the phospholipase C pathway known to be activated after P2U purinoceptor stimulation in DDT1 MF-2 cells. Pertussis toxin inhibited the action of these nucleotides on the cellular cAMP level. It can be concluded that the P2U purinoceptor in DDT1 MF-2 cells is coupled to different G-proteins, activating phospholipase C and inhibiting adenylyl cyclase activity.
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PMID:The phospholipase C activating P2U purinoceptor also inhibits cyclicAMP formation in DDT1 MF-2 smooth muscle cells. 780 68


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