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)

Recently, we demonstrated that aggregation of the high affinity IgE receptor in rat basophilic leukemia (RBL-2H3) cells results in rapid tyrosine phosphorylation of a 72-kDa protein (pp72). Here we investigated the relationship of pp72 phosphorylation to guanine nucleotide-binding protein (G protein) activation and phosphatidylinositol hydrolysis. The activation of G proteins by NaF in intact cells or by guanosine 5'-O-(3-thiotriphosphate) in streptolysin O-permeabilized cells induced both phosphatidylinositol hydrolysis and histamine release without tyrosine phosphorylation of pp72. Similarly, in RBL-2H3 cells expressing the G protein-coupled muscarinic acetylcholine receptor, carbachol activated phospholipase C and induced secretion without concomitant pp72 phosphorylation. Therefore, pp72 phosphorylation was not induced by G protein activation or as a consequence of phosphatidylinositol hydrolysis. To investigate whether pp72 tyrosine phosphorylation precedes the activation of phospholipase C, we studied the effect of the tyrosine kinase inhibitor genistein. Preincubation of cells with genistein decreased, in parallel, antigen-induced tyrosine phosphorylation of pp72 (IC50 = 34 micrograms/ml) and histamine release (IC50 = 31 micrograms/ml). However, genistein at concentrations of up to 60 micrograms/ml did not inhibit phosphatidylinositol hydrolysis nor did it change the amount of the secondary messenger inositol (1,4,5)-triphosphate. Previous observations showed that there was no pp72 tyrosine phosphorylation after activation of protein kinase C or after an increase in intracellular calcium. Taken together, these results suggest that pp72 tyrosine phosphorylation represents a distinct, independent signaling pathway induced specifically by aggregation of the Fc epsilon RI.
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PMID:Fc epsilon RI-induced protein tyrosine phosphorylation of pp72 in rat basophilic leukemia cells (RBL-2H3). Evidence for a novel signal transduction pathway unrelated to G protein activation and phosphatidylinositol hydrolysis. 137 2

Cross-linking of the B cell AgR results in activation of mature B cells and tolerization of immature B cells. The initial signaling events stimulated by membrane immunoglobulin (mIg) cross-linking are tyrosine phosphorylation of a number of proteins. Among the targets of mIg-induced tyrosine phosphorylation are the tyrosine kinases encoded by the lyn, blk, fyn, and syk genes, the mIg-associated proteins MB-1 and Ig-beta, phospholipase C-gamma 1 and -gamma 2, as well as many unidentified proteins. In this report we show that mIg cross-linking also regulates phosphatidylinositol 3-kinase (PtdIns 3-kinase), an enzyme that phosphorylates inositol phospholipids and plays a key role in mediating the effects of tyrosine kinases on growth control in fibroblasts. Cross-linking mIg on B lymphocytes greatly increased the amount of PtdIns 3-kinase activity which could be immunoprecipitated with anti-phosphotyrosine (anti-tyr(P) antibodies. This response was observed after mIg cross-linking in mIgM- and mIgG-bearing B cell lines and after cross-linking either mIgM or mIgD in murine splenic B cells. Thus, regulation of PtdIns 3-kinase is a common feature of signaling by several different isotypes of mIg. This response was rapid and peaked 2 to 3 min after the addition of anti-Ig antibodies. The anti-Ig-stimulated increase in PtdIns 3-kinase activity associated with anti-Tyr(P) immunoprecipitates could reflect increased tyrosine phosphorylation of PtdIns 3-kinase, increased activity of the enzyme, or both. In favor of the first possibility, the tyrosine kinase inhibitor herbimycin A blocked the increase in ant-Tyr(P)-immunoprecipitated PtdIns 3-kinase activity as well as the anti-Ig-induced tyrosine phosphorylation. Moreover, this response was not secondary to phospholipase C activation but rather seemed to be a direct consequence of mIg-induced tyrosine phosphorylation. Activation of the phosphoinositide pathway by a transfected M1 muscarinic acetylcholine receptor expressed in WEHI-231 B lymphoma cells did not increase the amount of PtdIns 3-kinase activity which could be precipitated with anti-Tyr(P) antibodies. Similarly, inhibition of the phosphoinositide pathway did not abrogate the ability of mIg cross-linking to stimulate this response. Thus, mIg-induced tyrosine phosphorylation regulates PtdIns 3-kinase, an important mediator of growth control in fibroblasts and potentially an important regulatory component in B cells as well.
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PMID:Membrane Ig cross-linking regulates phosphatidylinositol 3-kinase in B lymphocytes. 137 19

We report the molecular cloning of a fragment of human genomic DNA called S12, containing an open reading frame of 1170 nucleotides, which encodes a receptor for serotonin of 390 amino acids. The receptor function of the S12 protein was demonstrated by functional expression in mouse LS12 cells obtained by stable transfection of Ltk- cells, and LM5S12 cells, derived from LM5 cells (Ltk- cells previously transfected with the M5 muscarinic acetylcholine receptor). Adenylyl cyclase studies showed that the S12 receptor is able to mediate inhibition of adenylyl cyclase in response to serotonin in both types of cells. As studied in LM5S12 cells, the S12 receptor did not promote Ca2+ mobilization from internal stores, nor did it significantly modulate the sustained increase in [Ca2+]i elicited by stimulation of the phospholipase C stimulating M5 acetylcholine receptor. The pharmacologic profile of S12 as seen in adenylyl cyclase assays is as follows: (EC50 in nM): serotonin, full agonist (37 nM), 5-carboxamidotryptamine, full agonist (10 nM), sumatriptan, full agonist (50 nM), metergoline, partial agonist (10 nM), methysergide, partial agonist (40 nM), yohimbine, partial agonist (150 nM), metitepin, antagonist (KB = 0.7 to 1.2 nM). We propose that the human S12 serotonin receptor is a receptor of the 5-hydroxytryptamine1D subtype.
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PMID:Molecular cloning of a human serotonin receptor (S12) with a pharmacological profile resembling that of the 5-HT1D subtype. 155 93

The relationship between muscarinic receptor activation of phosphoinositide hydrolysis and the sequestration of cell surface muscarinic receptors has been examined for both intact and digitonin-permeabilized human SK-N-SH neuroblastoma cells. Addition of the aminosteroid 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino] hexyl]-1H-pyrrole-2,5-dione (U-73122) to intact cells resulted in the inhibition of oxotremorine-M-stimulated inositol phosphate release and of Ca2+ signaling by greater than 75%. In contrast, when phospholipase C was directly activated by the addition of the calcium ionophore ionomycin, inclusion of U-73122 had little inhibitory effect. Addition of U-73122 to intact cells also inhibited the agonist-induced sequestration of cell surface muscarinic receptors and their subsequent down-regulation with an IC50 value (4.1 microM) similar to that observed for inhibition of inositol phosphate release (3.7 microM). In contrast, when oxotremorine-M-stimulated phosphoinositide hydrolysis was inhibited by depletion of extracellular Ca2+, no reduction in the extent of receptor sequestration was observed. When introduced into digitonin-permeabilized cells, U-73122 more markedly inhibited inositol phosphate release elicited by either oxotremorine-M or guanosine-5'-O-(3-thiotriphosphate) than that induced by added Ca2+. Addition of oxotremorine-M to permeabilized cells resulted in muscarinic receptor sequestration and down-regulation. Both the loss of muscarinic acetylcholine receptors and activation of phosphoinositide hydrolysis in permeabilized cells were inhibited by the inclusion of guanosine-5'-O-(2-thiodiphosphate). The results indicate that the agonist-induced sequestration of muscarinic acetylcholine receptor in SK-N-SH cells requires the involvement of a GTP-binding protein but not the production of phosphoinositide-derived second messenger molecules.
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PMID:The aminosteroid U-73122 inhibits muscarinic receptor sequestration and phosphoinositide hydrolysis in SK-N-SH neuroblastoma cells. A role for Gp in receptor compartmentation. 166 Aug 86

Many hormones have been shown to activate phospholipase C, which results in the hydrolysis of membrane polyphosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (PIP2). Two second messengers are known to be produced by PIP2 hydrolysis, 1,2-diacylglycerol, an endogenous activator of a family of enzymes called protein kinase C (PKCs), and inositol 1,4,5-trisphosphate, which raises free levels of intracellular Ca2+. Treatment of various cells with 4 beta-phorbol 12-myristate 13-acetate (PMA), a specific exogenous activator of PKCs, causes an enhancement or sensitization of adenylyl cyclase activities. This finding prompted us to examine the effects of direct hormonal activation of PIP2 hydrolysis on the sensitization of adenylyl cyclase. Liao et al. [J. Biol. Chem. 265:11273-11284 (1990)] have shown that P2 purinergic receptor agonists such as ATP and muscarinic receptor agonists such as carbachol stimulate PIP2 hydrolysis in L cells expressing the M5 muscarinic acetylcholine receptor. We investigated the effects of these hormones on adenylyl cyclase and contrasted these effects with the sensitizing effects of PMA. We found that ATP pretreatment of two different types of L cells resulted in a rapid 50-150% sensitization of prostaglandin E1-, epinephrine-, and forskolin-stimulated adenylyl cyclase activity, with an EC50 of 3 microM ATP. This effect was qualitatively similar to that caused by 10 nM PMA. The enhancement of adenylyl cyclase activity was associated with an increase in the Vmax for hormonal stimulation and with a lack of significant effects of ATP on the EC50. The effect was completely eliminated when adenylyl cyclase was assayed in the presence of high free Mg2+ levels (10 mM). Down-regulation of PKCs with long term PMA treatment did not affect the ATP-induced sensitization of adenylyl cyclase, although the PMA-induced sensitization of adenylyl cyclase was eliminated. In contrast to the effects of ATP and PMA, treatment of the cells with carbachol alone had no effect on adenylyl cyclase; however, in combination with nanomolar concentrations of PMA, synergism of the sensitization of adenylyl cyclase was observed. These data indicate that the activation of P2 purinergic receptors by ATP, and possibly activation of M5 muscarinic receptors by carbachol, may be important in the signal transduction pathways leading to the increases in the responsiveness of hormone-stimulated adenylyl cyclase.
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PMID:Sensitization of adenylyl cyclase by P2 purinergic and M5 muscarinic receptor agonists in L cells. 192 86

Carbachol (CCh) a cholinergic agonist which hydrolyses phosphatidyl-inositol bisphosphate (PIP2) to produce the breakdown products inositol trisphosphate (IP3) and diacylglycerol (DAG) was tested for its ability to induce [3H]norepinephrine ([3H]NE) release and to accumulate [3H]inositol phosphate ([3H]IP) under normal and membrane depolarizing conditions. Our results suggest two major points: first, muscarinic acetylcholine receptor (mAChR) agonists and depolarizing agents (of which KCl is the most effective) act in concert to induce potentiation of PI turnover and potentiation of neurotransmitter release. The simultaneous presence of both a depolarizing agent and a receptor agonist is obligatory for eliciting potentiatory effect. Facilitation of release by muscarinic agonist and K+, added together, was 2 to 5-fold above additivity and the levels of [3H]IP accumulated were 3-5-fold above additivity by K+ and CCh. Enhancement of release and of [3H]IP formation is reversed by pirenzepine, a muscarinic (MI) specific antagonist, Kdiss = 0.4 and 0.8 microM, respectively. Second, synergy of IP accumulation in correlation with synergy of neurotransmitter release elicited by mAChR activation and membrane depolarization, suggests a possible role for phospholipase C (PLC) in the bifurcating control of neurotransmitter release and for the involvement of PLC and voltage sensitive channels in mediation of long-term potentiation (LTP).
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PMID:Potentiation of neurotransmitter release coincides with potentiation of phosphatidyl inositol turnover. A possible in vitro model for long term potentiation. 196 29

Because receptors, G proteins, and phospholipases all exist within a membrane lipid environment, it is not unreasonable to assume that an enzyme capable of changing the lipid environment can affect the coupling relationship among these signal transducing components. Our previous study showed that a muscarinic acetylcholine receptor regulates phosphatidylcholine phospholipase D via a G protein in brain. We demonstrate here that phosphatidylinositol phospholipase C and phosphatidylcholine phospholipase D are simultaneously activated within 15 s by muscarine in the presence of 1 microM GTP gamma S. More important, inhibition of phospholipase D by zinc attenuated carbamylcholine-induced activation of phospholipase C by 30%. Our additional evidence strongly indicates that the receptor-regulated phospholipase D plays an important modulatory role in agonist-stimulated phosphatidylinositol breakdown. This modulatory effect may be achieved by changing the membrane microenvironment in which phospholipase C and phosphoinositol lipids reside, consequently amplifying the inositol phospholipid signaling process. Our results lead us to postulate that the potential interaction between two different signaling pathways may provide a cell with intracellular coordination and enable the cell to achieve functional responses.
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PMID:Cross-talk between receptor-regulated phospholipase D and phospholipase C in brain. 200 91

The membrane signaling properties of the neuronal type-5 muscarinic acetylcholine receptor (M5 AChR) as expressed in murine L cells were studied. Recipient Ltk- cells responded to ATP acting through a P2-purinergic receptor by increasing phosphoinositide hydrolysis 2-fold but were unresponsive to 17 receptor agonists that are stimulatory in other cells. L cells expressing the M5 AChR responded to carbachol (CCh) with an approximately 20-fold increase in phospholipase C activity, mobilization of Ca2+ from endogenous stores, causing a transient peak increase in the intracellular concentration of Ca2+ ([Ca2+]i), influx of extracellular Ca2+, causing a sustained increase in [Ca2+]i dependent on extracellular Ca2+, and release of [3H]arachidonic acid from prelabeled cells, without altering resting or prostaglandin E1-elevated intracellular cAMP levels. None of the effects of the M5 AChR were inhibited by pertussis toxin. The regulation of L cell [Ca2+]i was studied further. ATP had the same effects as CCh and the two agonists acted on a shared intracellular pool of Ca2+. The peak and sustained [Ca2+]i increases were reduced by cholera toxin and forskolin, neither of which altered significantly phosphoinositide hydrolysis. This is consistent with interference with the action of inositol 1,4,5-trisphosphate (IP3) through cAMP-mediated phosphorylation and suggests a continued involvement of IP3 during the sustained phase of [Ca+]i increases. The temporal pattern of the sustained [Ca2+]i increase differed whether elicited by CCh or ATP, and was enhanced in pertussis toxin-treated cells. This is consistent with existence of a kinetic control of the sustained [Ca2+]i change by a receptor-G protein-dependent mechanism independent of the IP3 effector site(s) (e.g. pulsatile activation of phospholipase C and/or pulsatile activation of a receptor/G protein-operated plasma membrane Ca2+ channel). Thus, the non-excitable L cell may be a good model for studying [Ca2+]i regulations, as may occur in other nonexcitable cells of which established cell lines do not exist, and for studying of receptors that as yet cannot be studied in their natural environment.
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PMID:Cellular responses to stimulation of the M5 muscarinic acetylcholine receptor as seen in murine L cells. 216 42

The muscarinic acetylcholine receptor-mediated inhibition of adenylate cyclase was studied in slices of guinea-pig cerebral cortex under normal and depolarizing conditions. Carbachol (1 mM) inhibited basal and isoproterenol (50 microM)-stimulated cyclic AMP (cAMP) accumulation by 20% and 25%, respectively, in normal Krebs-Ringer bicarbonate buffer solution (KRB). High-K+ medium (42 mM K+) increased cAMP accumulation to 330% of the basal level and abolished the inhibitory effect of carbachol. It also abolished the effect of morphine, an agonist of opioid receptors. Low-Ca2+ KRB or the presence of the Ca2+ channel blocker nifedipine, counteracted the effect of high K+ and restored the inhibitory effect of carbachol on the cAMP level. Pretreatment of slices with W-7 or trifluoperazine, two calmodulin antagonists, had the same effect as low Ca2+ or nifedipine on high-K(+)-stimulated cAMP accumulation and caused reappearance of the inhibitory effects of carbachol and morphine. On the contrary, H-7, an inhibitor of protein kinase C, and neomycin, an inhibitor of phospholipase C, had no significant effect on high-K(+)-induced phenomena and did not restore the effect of carbachol. These data suggest that the Ca2(+)-calmodulin system activated by membrane depolarization regulates the cAMP level directly and also by affecting the receptor-mediated process in nerve cells.
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PMID:Disappearance in high-K+ medium of receptor-mediated inhibition of adenylate cyclase in guinea-pig cortical slices. 217 2

The classical scheme involving inositol phospholipid breakdown by phospholipase C as the sole source of diacylglycerol (DAG) has recently been challenged by evidence that phosphatidylcholine (PC) is an alternative source. In synaptic membranes of canine cerebral cortex, cholinergic agonists caused rapid accumulation of [3H]phosphatidic acid (PA) from [3H]PC within 15 s, whereas [3H]DAG formation showed a transient lag period before becoming elevated and then exceeding the amount of [3H]PA. Additional evidence shows that DAG is produced from PC by the action of phospholipase D to yield PA, which is further dephosphorylated to DAG by PA phosphatase. Our results indicate that this muscarinic acetylcholine receptor-regulated PC phospholipase D-PA phosphatase pathway may be a novel mechanism in cell signal transduction processes for activation of protein kinase C in brain.
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PMID:A novel mechanism for acetylcholine to generate diacylglycerol in brain. 240 58


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