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 ATP.Mg-dependent type-1 protein phosphatase and its activating factor (protein kinase FA) were identified to exist in brain synaptosome. The inactive protein phosphatase was found to exist in the synaptosomal cytosol whereas its activating factor (protein kinase FA) was present in the synaptosomal membrane, indicating that the inactive protein phosphatase and its activating factor FA are localized in two separate subcellular compartments. The membrane-bound FA was found to exist in two forms; approximately 75% of FA is inactive and trypsin-resistant, whereas 25% of FA is active and trypsin-labile. When membranes were incubated with exogenous phospholipase C, the inactive/trypsin-resistant FA could be activated and sequestered to become the active/trypsin-labile FA in a time- and dose-dependent manner. Taken together, the results provide initial evidence that the activation-sequestration of membrane-bound protein kinase FA may represent one mode of control modulating the activity of protein kinase FA and thereby to activate protein phosphatase in brain synaptosome, representing an efficient regulatory mechanism for regulating neurotransmission in the central nervous system.
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PMID:The mechanism of activation of protein kinase FA (the activator of type-1 protein phosphatase) in brain synaptosomes. 131 12

The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) has been shown to potentiate the stimulatory effect of ethanol on the hydrolysis of phosphatidylethanolamine (PtdEtn) in NIH 3T3 fibroblasts. Following an initial 20-min period, the main product of PtdEtn degradation in cells treated with TPA plus ethanol was ethanolamine phosphate. Here, we have examined the regulatory role of PKC and the possible catalytic role of phospholipase C in the formation of ethanolamine phosphate. TPA, bryostatin, and bombesin, direct or indirect activators of PKC, had similar potentiating effects on ethanol-induced formation of [14C]ethanolamine phosphate from [14C]PtdEtn in [14C]ethanolamine-prelabelled NIH 3T3 fibroblasts. At lower concentrations of ethanol (40-80 mM), significant stimulation of ethanolamine phosphate formation required longer treatments (2 h or longer). The combined effects of TPA (100 nM) and ethanol (50-200 mM) on ethanolamine phosphate formation were not inhibited by the PKC inhibitors staurosporine or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7). In contrast, these inhibitors significantly inhibited TPA-induced formation of ethanolamine, catalyzed by a phospholipase-D-type enzyme. In membranes isolated from TPA+ethanol-treated cells, enhanced formation of ethanolamine phosphate was maintained for at least 20 min. Down-regulation of PKC by prolonged (24-h) treatment of NIH 3T3 fibroblasts by 300 nM TPA enhanced, while overexpression of alpha-PKC in Balb/c fibroblasts diminished, the stimulatory effect of ethanol on the formation of ethanolamine phosphate. Finally, addition of the protein phosphatase inhibitor okadaic acid (2 microM) to fibroblasts inhibited TPA+ethanol-induced formation of ethanolamine phosphate. These results suggest that alpha-PKC-mediated protein phosphorylation may negatively regulate PtdEtn hydrolysis and that the potentiating effect of TPA may result, at least partly, from increased degradation of this PKC isoform.
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PMID:The long-term combined stimulatory effects of ethanol and phorbol ester on phosphatidylethanolamine hydrolysis are mediated by a phospholipase C and prevented by overexpressed alpha-protein kinase C in fibroblasts. 132 80

We have reviewed the literature, which supports an important role for dopamine withdrawal in the regulation of PRL secretion. Concentrations of dopamine in the hypophyseal portal circulation are sufficient to occupy the majority of dopamine receptors (1) and tonically suppress PRL secretion (20-26). Brief escapes from dopaminergic regulation associated with the secretion of PRL have been observed (37-41). Therefore, dopamine regulates secretion of PRL both by occupancy of, as well as dissociation from, specific D2 dopamine receptors. The rapid off rate from its receptor (2) is consistent with signals transmitted through brief decreases in dopamine concentration. The removal of dopamine for 10 min results in increases in intracellular cAMP and presumably activation of protein kinase A (39, 138) as well as activation of phospholipase C (137, 138) and protein kinase C (136). The removal of dopamine results directly in the release of PRL (37-41). Furthermore, the brief removal of dopamine results in the long-term potentiation of the PRL-releasing action of TRH (38-40). The potentiating action of dopamine withdrawal appears to be mediated by the activation of protein kinase A since pretreatment with VIP, a hormone that signals via protein kinase A, also potentiates the action of TRH (39). TRH stimulates PRL release via Ca2+/protein kinase C (177-184). The potentiating action of dopamine removal is selective for the Ca2+/protein kinase C pathway since dopamine removal does not potentiate the PRL-secreting action of VIP (38, 87, 92). The action of TRH is potentiated up to 30 min after the return of dopamine and the suppression of PRL to basal levels (38). In Fig. 10, dopamine dissociation from its receptor or VIP association to its receptor are shown separated by a broken line to indicate that by the time the potentiation of the action of TRH is tested, either dopamine is again occupying its receptor or VIP is no longer present. Therefore, the effect of protein kinase A activation is remembered by the lactotroph. We hypothesize that the responsiveness of the cell to TRH is potentiated by the phosphorylation of proteins by protein kinase A. Two potential substrates for protein kinase A are voltage-dependent Ca2+ channels and protein phosphatase inhibitors that would prolong the action of protein kinase C. When TRH occupies its receptor, intracellular Ca2+ levels are increased first from intracellular stores and subsequently by extracellular Ca2+ influx (187-189). Intracellular Ca2+ is mobilized by increased levels of IP3(128). Extracellular Ca2+ enters the lactotroph via voltage-dependent Ca2+ channels (189, 190).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion. 161 63

The mechanism of G protein-mediated sensitization of the contractile apparatus of smooth muscle to Ca2+ was studied in receptor-coupled alpha-toxin-permeabilized rabbit portal vein smooth muscle. To test the hypothesis that Ca2+ sensitization is due to inhibition of myosin light-chain (MLC) phosphatase activity, we measured the effect of guanosine 5'-[gamma-thio]triphosphate and phenylephrine on the rate of MLC dephosphorylation in muscles preactivated with Ca2+ and incubated in Ca(2+)- and ATP-free solution containing 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine (ML-9) to block MLC kinase activity. Guanosine 5'-[gamma-thio]triphosphate alone (300 microM) or in combination (3 microM) with phenylephrine decreased the rates of relaxation and dephosphorylation of MLC to about half of control values; this inhibition is sufficient to account for maximal G protein-mediated Ca2+ sensitization of MLC phosphorylation. The rate of thiophosphorylation of MLC with adenosine 5'-[gamma-thio]-triphosphate was not affected by guanosine 5'-[gamma-thio]triphosphate. We suggest that inhibition of protein phosphatase(s) by G protein(s) may have important regulatory functions.
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PMID:G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. 165 67

Protein kinase FA (an activating factor of ATP.Mg-dependent protein phosphatase) has been characterized to exist in two forms in the purified brain myelin. One form of kinase FA is spontaneously active and trypsin-labile, whereas the other form of kinase FA is inactive and trypsin-resistant, suggesting a different membrane topography with active FA exposed on the outer face of the myelin membrane and inactive FA buried within the myelin membrane. When myelin was solubilized in 1% Triton X-100, all kinase FA became active and trypsin-labile. Phospholipid reconstitution studies further indicated that when kinase FA was reconstituted in acidic phospholipids, such as phosphatidylinositol and phosphatidylserine, the enzyme activity was inhibited in a dose-dependent manner, suggesting that kinase FA interacts with acidic phospholipids which inhibit its activity. Furthermore, when myelin was incubated with exogenous phospholipase C, the inactive/trypsin-resistant FA could be converted to the active/trypsin-labile FA in a time- and dose-dependent manner. Taken together, it is concluded that membrane phospholipids play an important role in modulating the activity of kinase FA in the brain myelin. It is suggested that phospholipase C may mediate the activation-sequestration of inactive/trypsin-resistant kinase FA in the brain myelin through the phospholipase C-catalyzed degradation of acidic membrane phospholipids. The activation-sequestration of protein kinase FA may represent one mode of control modulating the activity of kinase FA in the central nervous system myelin.
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PMID:On the mechanism of activation of protein kinase FA (an activating factor of ATP.Mg-dependent protein phosphatase) in brain myelin. 216 Feb 45

The cytosolic fractions from epidermal growth factor (EGF)-treated A431 cells exhibit a marked increase in activities of ATP.Mg-dependent protein phosphatase and its activating factor (protein kinase FA) when compared to controls in the absence of EGF. By contrast, the Triton X-100-solubilized membrane fractions from the same EGF-treated cells exhibit a corresponding decrease in protein kinase FA activity. The EGF-dependent activation of protein kinase FA and ATP.Mg-dependent protein phosphatase occurred within physiological concentrations of EGF (ED50 = 5 x 10(-10) M). The changes of kinase and phosphatase activities which were measured concomitantly exhibit very similar characteristics as to EGF sensitivity and time dependence. The EGF-induced kinase and phosphatase activation occurred very rapidly, reaching the maximal activity levels within 3 min. Moreover, the EGF effect is transient; both EGF-stimulated phosphatase and kinase activities returned to control levels within 30 min. Taken together, the results suggest that EGF may induce the activation of kinase FA in the membrane and thereby promotes the activation of ATP.Mg-dependent phosphatase in the cytosol. Exposure of A431 cells to exogenous phospholipase C also resulted in the activation of endogenous kinase FA and ATP.Mg-dependent phosphatase in a similar pattern produced by EGF. This further suggests that phospholipase C can mimic EGF to mediate the activation of kinase FA and ATP.Mg-dependent phosphatase in A431 cells. By its dual role as a multisubstrate protein kinase and as an activating factor of multisubstrate protein phosphatase, protein kinase FA may represent a transmembrane signal of EGF.
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PMID:Epidermal growth factor induces activation of protein kinase FA and ATP.Mg-dependent protein phosphatase in A431 cells. 253 20

This review seeks to assemble recent discoveries about insulin receptor/kinase, guanine nucleotide-binding proteins, phosphatidyl inositol metabolism, and protein phosphatases to provide a mechanistic pathway by which insulin would alter carbohydrate and fat metabolism. It proposes a hypothetical chain of events that leads from the insulin receptor to protein phosphatase-1. The sequence starts with insulin binding to its receptor, activating the intrinsic receptor/kinase activity. The insulin receptor phosphorylates a guanine nucleotide-binding protein, which activates a particular phospholipase C. This in turn stimulates the production of two lipid-derived messengers: inositol-phospho-glucosamine and diacylglycerol. These messengers trigger the effects of insulin. The diacylglycerol produced by insulin is thought to be analogous to the diacylglycerol produced by alpha-adrenergic stimulation, which activates protein kinase C. Activation of this kinase could account for increases in phosphorylation of certain proteins. The inositol-phospho-glucosamine is the cytosolic messenger for insulin. One of the enzymes activated by insulin is protein phosphatase type-1. It is known that the phosphatase decreases phosphorylation of certain target enzymes. In response to insulin, activation of protein phosphatase type-1 occurs with a stable conformational change that may involve rearrangement of disulfide bonds. Rearrangement is either directly in response to the cytosolic messenger or is catalyzed by an isomerase activated by the insulin messenger. Ultimately, protein phosphatase type-1 and/or the disulfide isomerase may together mediate the pleiotropic effects of insulin on carbohydrate and fat metabolism.
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PMID:Proposal for a pathway to mediate the metabolic effects of insulin. 283 73

Effects of okadai acid (OA) on contractile force in rat uterine uterine muscles permeabilized with alpha-toxin were examined. (1) Contractile force activated by Ca2+(10(-6.5) M to 10(-4.4) M) was suppressed by relatively low concentrations of OA (30 to 300 nM). The suppressed force was further decreased after washed out of OA. (2)Addition of 10 microM OA enhanced force. Whereas, the increased tension level fell to less than the control level after washed out of OA. (3)Okadaic acid methyl ester (methyl okadaate), an OA derivative without protein phosphatase inhibition, did not affect contraction. These results suggest that the force-inhibiting effect of OA is a result of interference with contractile elements through inhibition of protein phosphatases (PPs) activity.
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PMID:Force-inhibiting effect of okadaic acid on skinned rat uterus permeabilized with alpha-toxin. 747 29

Intracellular recordings were obtained from myenteric AH neurons of guinea pig ileum in vitro. Slow excitatory synaptic responses associated with decreased potassium conductance (gK), inhibition of the spike afterhyperpolarization current (AHC), and increased chloride conductance (gCl) were mimicked by senktide, a neurokinin3 receptor agonist. Intracellular guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) decreased gK and increased gCl irreversibly after nerve stimulation or senktide application. Myenteric neurons in pertussis toxin (PTX)-treated tissues responded normally to senktide and nerve stimulation. Forskolin and phorbol 12,13-dibutyrate (PDBu) inhibited gK and the AHC but did not activate gCl. The AHC was not reduced by subthreshold concentrations of forskolin (10 nM) or PDBu (3 nM) alone but was inhibited by forskolin and PDBu applied together. Inhibitors of phospholipase C (D-609) or protein kinases (staurosporine) reduced slow synaptic and senktide responses. The protein phosphatase inhibitor, calyculin A, caused an inward current, a decrease in gK, and AHC inhibition but did not activate gCl. We conclude that slow excitatory synaptic responses are mediated by PTX-insensitive G proteins and activation of phospholipase C and protein kinases. Forskolin and PDBu activate pathways that inhibit gK. The mechanisms for activation of gCl are unknown.
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PMID:Signal-transduction pathways causing slow synaptic excitation in guinea pig myenteric AH neurons. 749 63

Human UC11 astrocytoma cells were used to investigate the role of protein kinase C (PKC) and other kinases in neurokinin (NK)1 receptor desensitization. The selective NK1 receptor agonist [Sar9,Met(O2)11]-substance P stimulated a biphasic accumulation of [3H]inositol phosphates ([3H]IPs) in the presence of 10 mM LiCl in cells that had been prelabeled with [3H]inositol. An initial rapid phase of [3H]IP accumulation during the first 1 min was followed by a slower sustained phase for up to 90 min. These results demonstrate that the human NK1 receptor desensitizes rapidly but only partially. The selective PKC inhibitor Ro31-8220 did not prevent rapid NK1 receptor desensitization but after a longer incubation significantly potentiated human NK1 receptor agonist-stimulated accumulation of [3H]IPs. These results suggest that, although PKC does not mediate the process of rapid desensitization, it does have an inhibitory role at later times. This conclusion is supported by studies with staurosporine, phorbol dibutyrate, and the protein phosphatase inhibitor okadaic acid. Studies using AlF4-, an agent that can directly activate G proteins, and Ro31-8220 suggested that PKC can exert inhibitory effects 'downstream' of receptor activation, although immunoprecipitation of the G proteins alpha q/alpha 11 demonstrated that they do not undergo phosphorylation in UC11 cells and are unlikely to be the target of PKC-mediated inhibitory feedback. Delayed inhibitory feedback by PKC may be mediated by phosphorylation of phospholipase C, although an additional site of action on the NK1 receptor cannot be ruled out.
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PMID:Protein kinase C mediates delayed inhibitory feedback regulation of human neurokinin type 1 receptor activation of phospholipase C in UC11 astrocytoma cells. 752 12


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