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 protein kinase C activation in a coupling of Ca2+-mobilizing receptors/GTP-binding protein/phospholipase C was examined using Xenopus oocytes before and after microinjection of mRNA purified from rat brains. Under voltage-clamp conditions, although the phorbol ester TPA per se never elicited any changes in ionic conductance, chloride current responses of mRNA-injected cells to 5-hydroxytryptamine and acetylcholine (ACh) were suppressed by an 8-min pretreatment of 12-O-tetradecanoyl-4 beta-phorbol-13-acetate (TPA), at nanomolar concentrations. Native ACh response in intact follicular oocytes was also inhibited by the TPA treatment. However, similar current responses triggered by the direct activation of their intracellular signalling pathway with guanosine-5'-O-(3-thio)triphosphate or Ca2+ were not affected by TPA. Biochemical analyses indicated that phosphorylation of 33,000- and 45,000-dalton proteins was markedly enhanced by TPA in vivo, and that stimulation of receptors with agonists as well as TPA treatment increased phosphoproteins in the membrane fraction of mRNA-injected oocytes. These observations suggest that protein kinase C may switch off the signal transduction from receptors to GTP-binding proteins and may participate in the negative feedback modulation of receptor-operated ion channel responses.
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PMID:Phorbol ester inhibition of current responses and simultaneous protein phosphorylation in Xenopus oocyte injected with brain mRNA. 333 51

The platelets of a young man with the grey platelet syndrome were severely depleted of all seven alpha-granule proteins assayed as well as partially deficient in alpha-mannosidase and alpha-fucosidase; four other lysosomal enzymes were present in normal concentrations. Total platelet 5-hydroxytryptamine (5HT) and adenine nucleotides were normal, and 14C-5HT uptake reached normal levels only slightly more slowly than a control. Aggregation and dense body secretion occurred normally in response to ADP, adrenaline, collagen, PAF-acether, sodium arachidonate, A23187, Ionomycin, TPA and U44069, but were very delayed in response to thrombin. The increase in cytosolic free calcium in response to thrombin was very slow and much reduced in amplitude, whether in the presence or absence of extracellular Ca2+. These defects in response to thrombin were not corrected by the separate addition of purified alpha-granule proteins or by a whole releasate from normal platelets. It is suggested that these platelets, in addition to their alpha-granule deficiency, may have a specific defect of thrombin receptor-mediated activation of phospholipase C.
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PMID:Grey platelet syndrome: studies on platelet alpha-granules, lysosomes and defective response to thrombin. 358 Mar

Addition of GTP markedly enhances the ability of thrombin to cause a leftward shift in the Ca2+ dose/response curve for 5-hydroxytryptamine secretion from permeabilised human platelets. Little effect is observed on addition of GTP in the absence of thrombin. Neither ADP nor adrenaline, in the presence or absence of GTP, causes such a shift, whereas 5-hydroxytryptamine does so to a small extent but only in the presence of GTP. The leftward shift in the Ca2+ dose/response curve induced by 12-O-tetradecanoyl-phorbol-13-acetate or 1-oleyl-2-acetylglycerol is not enhanced by addition of GTP. The thrombin concentration required for half-maximal enhancement of the response to Ca2+ is markedly reduced by addition of GTP. The results support the postulate that the effects of excitatory agonists in this system correlate with their ability to activate phospholipase C and provide further evidence for a role for GTP in signal transduction between the receptor and phospholipase C.
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PMID:Effect of various excitatory agonists on the secretion of 5-hydroxytryptamine from permeabilised human platelets induced by Ca2+ in the presence or absence of GTP. 387 12

The salivary glands of adult blowflies (Calliphora erythrocephala) contain enzymes that hydrolyse phosphatidylinositol, predominantly by a Ca2+-independent deacylation, though a Ca2+-dependent phosphodiesterase (phospholipase C) activity could be detected. The deacylating enzymes could also hydrolyse phosphatidylcholine and phosphatidylethanolamine, and were secreted in the saliva. Homogenization of salivary glands prelabelled with [3H]inositol resulted in a rapid deacylation of the endogenous 3H-labelled phosphatidylinositol; this hydrolysis was unaffected by addition of 5-hydroxytryptamine to the homogenate.
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PMID:Phosphatidylinositol-hydrolysing enzymes in blowfly salivary glands. 628 18

Cyclic AMP and Ca2+ are intracellular mediators of hormone action. Catecholamines interact with beta adrenoceptors to activate adenylate cyclase or with alpha 2 adrenoceptors to inhibit adenylate cyclase. Alpha 1 adrenoceptor activation results in elevation of cytosol Ca2+ and an increased breakdown of phosphatidylinositol. In blowfly salivary glands, 5-hydroxytryptamine (5-HT) interacts with beta type receptors resulting in adenylate cyclase activation while alpha type receptors are involved in phosphatidylinositol breakdown and elevation of cytosol Ca2+. The link between Ca2+ mobilization and phosphatidylinositol breakdown remains to be established but breakdown of the receptor-regulated pool of phosphatidylinositol is not secondary to the rise in Ca2+. Direct addition of 5-HT to cell-free homogenates of blowfly salivary glands results in activation of phosphatidylinositol breakdown in the absence of Ca2+. In rat liver plasma membrane preparations, vasopressin increases phosphatidylinositol breakdown in the absence of Ca2+ or cytosol if deoxycholate is present. The data do not indicate whether hormone activation increases the availability of substrate to enzymatic hydrolysis or activates phospholipase C. However, they demonstrate that hormones directly accelerate phosphatidylinositol breakdown.
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PMID:Hormonal regulation of phosphatidylinositol breakdown. 630 22

In blowfly salivary glands, 5-hydroxytryptamine stimulated a rapid and sustained loss of [3H]inositol, [32P]phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate. There was a corresponding increase in labeled inositol phosphates. In the absence of Ca2+, 5-hydroxytryptamine stimulated a rapid but transient loss of labeled phosphatidylinositol 4,5-bisphosphate. By 5 min, the amount of labeled phosphatidylinositol 4,5-bisphosphate recovered to control values. The divalent ionophore A23187 stimulated loss of labeled phosphatidylinositol 4,5-bisphosphate and increased the amount of labeled phosphatidylinositol. In homogenates, Ca2+ stimulated phosphatidylinositol 4,5-bisphosphate breakdown but not phosphatidylinositol breakdown. These results suggest that hormone-stimulated breakdown of labeled phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate occurs through a phospholipase C and is relatively independent of extracellular Ca2+. There is also a Ca2+-activated conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol.
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PMID:Phosphoinositide breakdown in blowfly salivary glands. 632 Jun 53

To clarify the involvement of botulinum ADP-ribosyltransferase sensitive low molecular G-proteins in 5-hydroxytryptamine (5-HT)-induced stimulation of phosphatidylinositol turnover, we examined the effects of 5-HT on inositol phosphates formation in COS 7 cells transfected with 5-HT2c receptor cDNA, but did not in non-transfected or vector-transfected cells. A typical 5-HT2c receptor antagonist mianserin (0.3-3 microM) inhibited the 5-HT-induced inositol phosphates formation. Treatment with botulinum toxin D preparation (20 micrograms/ml, 8 h) that contained botulinum C3 ADP-ribosyltransferase, blocked the 5-HT-induced inositol phosphate formation, although botulinum toxin A preparation that did not contain the enzyme did not have an influence. These results support our previous findings suggesting that low molecular weight G-proteins ADP-ribosylated by botulinum ADP-ribosyltransferase are involved in phospholipase C activity.
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PMID:Possible involvement of botulinum ADP-ribosyltransferase sensitive low molecular G-protein on 5-hydroxytryptamine (5-HT)-induced inositol phosphates formation in 5-HT2c cDNA transfected cells. 762 49

Desensitization of platelets to 5-hydroxytryptamine (5HT) (1 microM), during active removal of the agonist by the platelet 5HT-uptake system, was studied at the level of signal transduction. Desensitization to 5HT was dose-dependent and homologous. Without occupation of the 5HT2 receptor, neither an increase in cytosolic [Ca2+] (30 nM ionomycin), nor a separate or simultaneous activation of protein kinase C (by 10 microM 1-oleoyl-2-acetylglycerol), could induce desensitization to 5HT (1 microM). During the early phase of desensitization, the 5HT2 receptor was coupled to phospholipase C, whereas during the late phase of desensitization this coupling was disconnected. However, after disappearance of the agonist, the coupling in the resting platelet recovered quickly, and was nearly complete (82%) after 30 min. During this resensitization, the 5HT-inducibility of activation of phospholipase C, of the increase in cytosolic [Ca2+] and of stimulation of protein kinase C were restored in parallel. The time course for resensitization of the 5HT-induced increase in cytosolic [Ca2+] was independent of the presence of extracellular Ca2+. It is concluded that, after dissociation of 5HT from the platelet 5HT2-receptor, 5HT-induced responses rapidly resensitize. Because of its short duration and the parallelism in recovery between the different 'down-stream phospholipase C' intracellular transduction signals, it is considered that desensitization arises from a reversible change in the transduction mechanism at a step up to or including the activation of phospholipase C. Neither desensitization nor resensitization to 5HT is dependent on the presence of extracellular Ca2+.
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PMID:Desensitization and resensitization of human platelets to 5-hydroxytryptamine at the level of signal transduction. 774 8

The direct effect of melatonin and related agonists on Li(+)-amplified phosphoinositide breakdown was studied in chick brain slices prelabeled with myo-[2-3H]-inositol. The melatonin receptor agonist 6-chloromelatonin (10-100 microM) increased, in a concentration-dependent manner, the accumulation of inositol phosphates (IP) in chick brain slices. This effect of 6-chloromelatonin (10 microM) was rapid as transient increases in IP3/IP4 (maximal increase, 29% at 20 s) and IP2 levels (maximal increase, 36% at 1 min) were observed, followed by a slower but sustained increase in IP1 level (30% at 5 min), when the amount of IP3/IP4 and IP2 had already been decreased to the control level. The phosphoinositide response elicited by 6-chloromelatonin (10 microM) was dependent on the presence of extracellular calcium. Direct stimulation of membrane phospholipase C by 6-chloromelatonin (10 microM) in isolated myo-[2-3H]inositol-prelabeled optic tectum membranes was dependent on the presence of guanosine-5'-O-(3-thio)triphosphate (1 microM), thus suggesting that G protein(s) link melatonin receptor activation to phospholipase C stimulation. The competitive melatonin receptor antagonist luzindole (10-100 microM) inhibited in a concentration-dependent manner the IP1 accumulation stimulated by 6-chloromelatonin (10-100 microM); however, it did not affect the accumulation stimulated by 5-hydroxytryptamine (10 microM). By contrast, methysergide (10 microM) completely inhibited 5-hydroxy-tryptamine (10 microM)-, but not 6-chloromelatonin (10 microM)-, induced IP1 accumulation. Melatonin receptor agonists increased IP1 accumulation in a concentration-dependent manner reaching different maximal responses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Melatonin receptor-mediated stimulation of phosphoinositide breakdown in chick brain slices. 779 6

The pharmacological profile of coupling of the cloned human serotonin [5-hydroxytryptamine] (5-HT)1E receptors to second messengers was studied in African green monkey kidney cells (BS-C-1). At low concentrations (0.1-100 nM), 5-HT inhibited forskolin-stimulated cAMP accumulation (FSCA) by up to 90% whereas at higher concentrations it potentiated FSCA; potentiation was dependent on receptor density. Pretreatment of cells with pertussis toxin (PTx) or cholera toxin (CTx) eliminated agonist-induced inhibition and potentiation of FSCA, respectively. The potentiation of FSCA was not due to activation of phospholipase C and/or phospholipase A2 since 5-HT had no effect on inositol phosphate release, intracellular Ca2+ mobilization or arachidonic acid mobilization; neither was it affected by pretreatment with the nonselective phospholipase A2 inhibitor, quinacrine, or by the removal of extracellular Ca2+. The pharmacological profiles of the 5-HT1E receptor-mediated inhibition and potentiation of FSCA were very similar, although agonists displayed higher affinity for the former. These results indicate that the human 5-HT1E receptors can potentially couple, with similar pharmacological profiles, to multiple effector pathways. However, the potency and intrinsic activity of the compounds eliciting these responses can differ significantly, depending on the receptor density and the effector pathway studied.
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PMID:The cloned human 5-HT1E receptor couples to inhibition and activation of adenylyl cyclase via two distinct pathways in transfected BS-C-1 cells. 798 78


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