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 change in transmembrane potential of rat adipocytes was measured using the fluorescent probe 3,3'-diethylthiadicarbocyanine iodide, diS-C2-(5). The method was calibrated by altering the potassium ion concentration while keeping the sum of potassium and sodium ions at a constant concentration of 153 mM (Bailey et al: Bioelectrochem. Bioenergetics 21:333-42, 1989). Two insulin-mimetic agents, phospholipase C from Clostridium perfringens and concanavalin A, induced a dose dependent hyperpolarization of rat epididymal adipocytes, like insulin. Removal of endogenous adenosine with adenosine deaminase or adenosine receptor blockade with isobutylmethylxanthine following the initiation of insulin-induced hyperpolarization resulted in depolarization. These same agents induced hyperpolarization of -6 to -8 mV when added without insulin. The replacement of adenosine with its analogue, N6-phenylisopropyladenosine, plus insulin depolarized the cells toward the transmembrane potential established by insulin, -2.0 mV. These studies suggest that adenosine receptor occupancy is required to maintain insulin-induced hyperpolarization.
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PMID:Membrane potential of rat adipocytes: effect of phospholipase C, concanavalin A, and adenosine. 751 7

Blockade of adenosine receptors by 3-isobutyl-1-methylxanthine or degradation of endogenous adenosine with adenosine deaminase increased the phosphatidylcholine concentration in isolated rat adipocyte plasma membranes, an effect which was suppressed by the phosphatidylethanolamine methyltransferase inhibitor, S-adenosyl-L-homocysteine, and reversed by the adenosine analogue, N6-(L-phenylisopropyl)-adenosine. For example, the addition of N6-(L-phenylisopropyl)-adenosine to adenosine deaminase pretreated plasma membranes rapidly lowered the concentration of phosphatidylcholine by 171 nmol/mg at 30 seconds compared to control. Insulin-induced stimulation of phospholipid methylation in membranes treated with 3-isobutyl-1-methylxanthine or adenosine deaminase was achieved only after the addition of N6-(L-phenylisopropyl)-adenosine. These results suggest that adenosine receptor occupancy inhibits phospholipid methylation, is required for insulin stimulation of phospholipid methylation, and may perhaps activate a phosphatidylcholine-specific phospholipase C or phospholipase D.
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PMID:Insulin and adenosine regulate the phosphatidylcholine concentration in isolated rat adipocyte plasma membranes. 754 81

CTLL-2 cells are a clone of CTL that are dependent on IL-2 for proliferation. In addition to various cytokine receptors, we observed that these cells express three subtypes of adenosine receptors (ARs). In an initial attempt to delineate the functions of these receptors in CTLL-2 cells, we tested their role in proliferation. Elimination of endogenous adenosine with adenosine deaminase (ADA) markedly suppressed IL-2-dependent proliferation of these cells. This proliferative response was restored by addition of R-phenylisopropyladenosine (R-PIA), a non-hydrolyzable adenosine analogue. The stimulatory response to R-PIA was attenuated following blockade of ARs by 0.5 mM theophylline and 10 microM BW-A1433, but not by blockade of the A1AR with 100 nM xanthine amine congener. The rank order of potency of adenosine analogues in proliferation assays was R-PIA > or = N-ethylcarboxamide adenosine > S-PIA > PAPA-APEC (a substituted ethylamino-5'-N-ethylcarboxamidoadenosine). These data suggest a potential role of the A3AR in the proliferative response. R-PIA stimulates production of 1,4,5-inositol trisphosphate in CTLL-2 cells, suggesting a role of the phospholipase C signaling pathway in the proliferative response. A23187 (100 nM) and phorbol 12,13 dibutyrate (10 nM), but not 4 alpha-phorbol (10 nM), were able to restore IL-2-dependent CTLL-2 proliferation in the presence of ADA. Furthermore, inhibition of protein kinase C by staurosporine (10 nM) and of phospholipase C by tricyclodecan-9-yl-xanthogenate (D609) blocked R-PIA-mediated cell proliferation. These data demonstrate an obligatory role of adenosine in IL-2-dependent proliferation of CTLL-2 cells and support the involvement of an AR-stimulated phospholipase C signaling pathway in this process.
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PMID:Adenosine acts as an endogenous modulator of IL-2-dependent proliferation of cytotoxic T lymphocytes. 767 97

As shown on cultured astrocytes from the mouse, in the presence of adenosine deaminase, 2-chloroadenosine by acting on A1-adenosine receptors potentiated the activation of phospholipase C induced by the alpha 1-adrenergic agonist, methoxamine. This potentiation required the presence of external calcium and was blocked by pertussis toxin. Moreover, this potentiation resulted from a cascade of events: activation (by calcium and protein kinase C) of a phospholipase A2 coupled to A1-adenosine receptors, release of arachidonic acid, which inhibited the reuptake of glutamate into astrocytes and finally additional activation of phospholipase C by externally accumulated glutamate through metabotropic receptors. The effects of 2-chloroadenosine and methoxamine were respectively mimicked by somatostatin and substance P while endothelins reproduced the combined effects of 2-chloroadenosine and methoxamine. Conditioned media from treated astrocytes enriched in glutamate stimulated phospholipase C in cultured striatal neurones. In addition, glutamate alone was also found to stimulate phospholipase A2 in astrocytes through receptors exhibiting a pharmacological profile distinct from metabotropic receptors coupled to phospholipase C and the glutamate response was potentiated by ATP. Moreover, the neuronal arachidonic acid production evoked by glutamate was potentiated by acetylcholine. Finally, the combined application of 2-chloroadenosine and methoxamine on striatal astrocytes reduced the permeability of gap junctions between astrocytes and this response was mimicked by arachidonic acid. Together, these results emphasized the contribution of astrocytes in the regulation of glutamatergic transmission.
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PMID:Glial receptors and their intervention in astrocyto-astrocytic and astrocyto-neuronal interactions. 792 48

ATP is a well-known inducer of prostacyclin and nitric oxide release from vascular endothelial cells. These responses are mediated by P2 receptors coupled to a phospholipase C. We have investigated the influence of ATP on the control of adenosine 3',5'-cyclic monophosphate (cAMP) in bovine aortic endothelial cells. ATP produced a slight increase in the cAMP content of unstimulated endothelial cells. A more impressive response to ATP (5-fold) was observed in forskolin-stimulated cells. The rank orders of potency of various ATP analogues were strikingly different for the increase in cAMP and the accumulation of inositol phosphates. The action of ATP was unaffected by indomethacin. Protein kinase C downregulation produced only a partial inhibition of the ATP response. The effect of phorbol 12-myristate 13-acetate and bradykinin on the forskolin-induced accumulation of cAMP was much smaller than that of ATP. Neither adenosine deaminase nor AMP deaminase decreased the response to ATP, which thus cannot result from the ATP degradation into adenosine. However, 8-(p-sulfophenyl)theophylline inhibited the responses to both ATP and adenosine. In conclusion, ATP enhances the accumulation of cAMP in endothelial cells. This action appears to be the sum of two components: a minor one resulting from kinase C activation and a major one mediated either by a direct interaction of ATP with A2 receptors, or by putative methylxanthine-sensitive P2 receptors.
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PMID:Enhancement of endothelial cAMP accumulation by adenine nucleotides: role of methylxanthine-sensitive sites. 838 57

Extracellular adenosine triphosphate (ATP) has a range of effects on a wide variety of cells through the activation of specific purinoceptors. The aim of this study was to establish whether P2 purinoceptors are present on airway smooth muscle cells. Experiments were conducted on cultured rat tracheal smooth-muscle cells (first through third passage). Intracellular Ca2+ ([Ca2+]i) was measured using Fura-2 and dual-excitation wavelength microfluorometry. The effects of ATP, adenosine diphosphate (ADP), uridine triphosphate (UTP), and adenosine (ADO) were measured in concentrations from 10(-6) to 10(-3) M. At a concentration of 10(-4) M, the peak [Ca2+]i was 502 +/- 92 nM for ATP and 543 +/- 76 nM for UTP (mean +/- standard error of the mean). ADO had no significant effect on Ca2+ release. Peak [Ca2+]i induced by ATP was not dependent on extracellular Ca2+ but was blocked by U-73122, an inhibitor of phospholipase C. Pretreatment with adenosine deaminase and desensitization with alphabeta-MeATP had no effect on ATP-induced Ca2+ release. The effects of ATP (10(-4) M) on peak [Ca2+]i were potentiated by the presence of ADO 10(-5) M (969 +/- 257 nM; P < 0.05). The presence of XAC, a blocker of A1 and A2 ADO receptors did not prevent this effect. In the presence of XAC, ADO 10(-6) M potentiated the effects of ATP (peak [Ca2+]i: 1,300 +/- 229 nM). The addition of 1433U83, a blocker of A3 ADO receptors, blocked the synergistic effect of ADO 10(-6) M on ATP. These data show that P2 purinoceptors, most likely of the P2U subtype, are present on airway smooth muscle cells and that the newly discovered A3 ADO receptor appears to be also present.
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PMID:Effects of purine nucleotides and nucleoside on cytosolic calcium levels in rat tracheal smooth muscle cells. 903 28

ATP stimulation of surfactant secretion in type II cells is mediated by both a P2Y2 receptor coupled to phospholipase C and a receptor coupled to adenylate cyclase. UTP also activates the P2Y2 receptor but does not stimulate adenosine 3',5'-cyclic monophosphate (cAMP) formation. We have examined surfactant secretion and signaling parameters in response to ATP and UTP in type II cells from newborn rats. There was a developmental increase in the response to both agonists. However, whereas ATP increased secretion as early as day 1, the effect of UTP did not become significant until 4 days after birth. ATP increased cAMP formation as early as day 1 but did not promote diacylglycerol formation or phospholipase D activation until day 4. Thus the adenylate cyclase-coupled ATP signaling mechanism is functional early in development but the P2Y2 pathway is not. We therefore used type II cells from 1- to 2-day-old rats to investigate the adenylate cyclase-coupled mechanism in the absence of interactions with the P2Y2 system. Effects of ATP and 5'-(N-ethylcarboxamido)adenosine (NECA) on surfactant secretion and cAMP formation were not additive, and their effects on secretion were antagonized by the same adenosine receptor antagonists. Overnight culture of the cells with NECA almost completely abolished the subsequent increase in cAMP formation in response to NECA, adenosine, and ATP but not to terbutaline. These data suggest that ATP, NECA, and adenosine activate the same receptor. Effects of ATP were not decreased by adenosine deaminase, showing that they are not mediated by adenosine acting directly at adenosine receptors. We suggest that ATP directly activates an adenosine receptor on the type II cell.
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PMID:Adenylate cyclase-coupled ATP receptor and surfactant secretion in type II pneumocytes from newborn rats. 912 68

Several candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) map on chromosome 20, including the phosphoenolpyruvate carboxykinase gene (PCK1) and one of the maturity onset diabetes of the young genes (MODY1). Thus, we have investigated the entire long arm of chromosome 20. Linkage analyses were conducted in a total sample of 148 NIDDM families (301 NIDDM sib pairs) and in a subset of 42 early onset NIDDM families, where genetic components are likely to play a more important role (55 NIDDM sib pairs diagnosed at or before 45 years of age), using 10 highly polymorphic markers with an average map density of 7.5 cM. Using affected sib pair methods (two-point linkage and multipoint linkage analyses), significant results were obtained with the 20q13 region, in the vicinity of the PCK1 locus, only in the subset of 55 early onset NIDDM sib pairs (multipoint MLS = 2.74, P = 0.0004; MLS = 2.34, P = 0.0009 when using a conservative weighting procedure). Moreover, another region spanning the ribophorin II (RPNII, phospholipase C (PLC1) and adenosine deaminase (ADA) loci suggested linkage with NIDDM (multipoint MLS of 1.81 in all NIDDM sib pairs, P = 0.003; MLS = 1.31, P = 0.012 when using a conservative weighting procedure). Whereas our study suggests the location of a susceptibility locus for early onset NIDDM in the PCK1 gene region, further investigation in larger data sets is required to confirm these results and assess the role of other regions on chromosome 20q in human NIDDM.
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PMID:A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. 928 75

We have investigated the effect of endogenous adenosine on the release of [3H]acetylcholine ([3H]ACh) in cultured chick amacrine-like neurons. The release of [3H]ACh evoked by 50 mM KCl was mostly Ca2+ dependent, and it was increased in the presence of adenosine deaminase and in the presence of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptor antagonist. The effect of adenosine on [3H]ACh release was sensitive to pertussis toxin (PTX) and was due to a selective inhibition of N-type Ca2+ channels. Ligand binding studies using [3H]DPCPX confirmed the presence of adenosine A1 receptors in the preparation. Using specific inhibitors of the plasma membrane adenosine carriers and of the ectonucleotidases, we found that the extracellular accumulation of adenosine in response to KCl depolarization was due to the release of endogenous adenosine per se and to the extracellular conversion of released nucleotides into adenosine. Activation of adenosine A1 receptors was without effect on the intracellular levels of cyclic AMP under depolarizing conditions, but it inhibited the accumulation of inositol phosphates. Our results indicate that in cultured amacrine-like neurons, the Ca2+-dependent release of [3H]ACh evoked by KCl is under tonic inhibition by adenosine, which activates A1 receptors. The effect of adenosine on the [3H]ACh release may be due to a direct inhibition of N-type Ca2+ channels and/or secondary to the inhibition of phospholipase C and involves the activation of PTX-sensitive G proteins.
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PMID:Modulation of [3H]acetylcholine release from cultured amacrine-like neurons by adenosine A1 receptors. 972 33

The effect of ATP in human and rabbit corpus cavernosum (CC) smooth muscle was investigated. Strips of human CC were vertically mounted in an organ bath and the tonic tension was recorded. ATP (0.1-3 mM) induced a concentration-dependent relaxant effect, with a pD2 value of 3.01+/-0.3. The purine-induced relaxation was not affected by L-NAME (100 microM). In rabbit CC, ATP also induced a concentration-dependent relaxation, which was not influenced by L-NAME or by indomethacin (3 microM), with a pD2 value of 3.1 +/-0.4. The ATP-induced relaxant effect in rabbit CC was increased by both the inhibitor of adenosine reuptake, dipyridamole (3 microM) and by the inhibitor of adenosine deaminase, EHNA (0.3 microM). Moreover CGS 15943 (3 microM), an A2a adenosine antagonist, reduced the ATP-induced relaxation. UTP was not able to produce relaxation. The two ATP analogues 2-methylthioATP and alpha,beta-methylene ATP were able to induce relaxation in rabbit CC, with the following order of potency: 2-methylthioATP > ATP > alpha,beta-methylene ATP thus suggesting a role for P2y receptors. However, reactive blue (500 microM), an unspecific P2y antagonist, did not modify the ATP relaxant response. The inhibition of phospholipase C by U73122 (3 microM) and of the endoplasmic reticulum Ca2+ATPase by thapsigargin (1 microM) did not modify the ATP-induced relaxation. The P2x specific antagonist PPADS (30 microM) and suramine (500 microM) were not able to modify the ATP relaxation either in the absence or presence of CGS 15943 (3 microM). These results confirm that ATP acts as a potent and NO-independent relaxant agent of human and rabbit CC. Our findings also show that the ATP effect is partially attributable to the metabolic breakdown of ATP to adenosine, which acts through A2a receptor stimulation, but is also due to a direct stimulation of P2 receptors that are different from the classical P2y and P2X receptor subtypes for ATP.
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PMID:Studies on the mechanisms involved in the ATP-induced relaxation in human and rabbit corpus cavernosum. 1003 32


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