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)

Previous studies have demonstrated enhanced phosphorylation of phospholipase C-tau (PLC-tau), a key regulatory enzyme in phosphoinositide metabolism, in cells treated with platelet-derived growth factor (PDGF) and epidermal growth factor, both of which act via specific receptor tyrosine kinases. Our studies on BALB/c-3T3 cells show that agents that promote cellular cyclic AMP accumulation also increase the phosphorylation, specifically the serine phosphorylation, of this enzyme. Increased phosphorylation of PLC-t (2-3-fold) was evident within 5-10 min of addition of isobutylmethylxanthine (IBMX) and either cholera toxin or forskolin to cells, and persisted for at least 3 h. Treatment of cells with cyclic AMP agonists also enhanced, with similar kinetics, the phosphorylation of a 76 kDa protein co-precipitated by anti-PLC-tau monoclonal antibodies. Brief exposure of cells to cholera toxin/IBMX or forskolin/IBMX decreased inositol phosphate formation induced by the GTP-binding protein (G-protein) activator aluminium fluoride by approx. 50%, but was without effect on PDGF-stimulated inositol phosphate formation. These findings suggest that PLC-tau, and perhaps the 76 kDa co-precipitated protein, are substrates of cyclic AMP-dependent protein kinase in BALB/c-3T3 cells: however, the lack of effect of cyclic AMP elevation on PDGF-stimulated inositol phosphate formation indicates that the intrinsic activity of PLC-tau is unaltered by cyclic AMP-mediated phosphorylation.
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PMID:Cyclic AMP agonists induce the phosphorylation of phospholipase C-tau and of a 76 kDa protein co-precipitated by anti-(phospholipase C-tau) monoclonal antibodies in BALB/c-3T3 cells. Relationship to inositol phosphate formation. 170 22

When loaded alongside GTP-gamma-S into ATP-permeabilized cells, neomycin, at concentrations below 1 mM, inhibits GTP-gamma-S-induced histamine secretion and phosphatidic acid formation (Cockcroft, S., and B. D. Gomperts, 1985. Nature (Lond.). 314: 534-536; Aridor, M., L. M. Traub, and R. Sagi-Eisenberg. 1990. J. Cell Biol. 111:909-917). However, at higher concentrations internally applied neomycin induces histamine secretion in a process that is: (a) dose dependent; (b) dependent on the internal application of GTP; (c) independent of phosphoinositide breakdown; and (d) inhibited by pertussis toxin (PtX) treatment. These results indicate that neomycin can stimulate histamine secretion in a mechanism that bypasses phospholipase C (PLC) activation and yet involves a PtX-sensitive GTP-binding protein (G protein). Unlike its dual effects, when internally applied, neomycin induces histamine secretion from intact mast cells in a dose-dependent manner. Half-maximal and maximal effects are obtained at 0.5 and 1 mM neomycin, respectively. This process is rapid (approximately 30 s), is independent of external Ca2+, and is associated with phosphatidic acid formation, implying that neomycin can activate histamine secretion by a mechanism similar to that utilized by other basic secretagogues of mast cells. Neomycin stimulates fourfold the GTPase activity of cholate-solubilized rat brain membranes in a PtX-inhibitable manner. In addition neomycin, as well as the basic secretagogues of mast cells, compound 48/80, and mastoparan, significantly reduce (by approximately 80%) the ADP ribosylation of PtX substrates present in rat brain membranes. Taken together these data suggest that neomycin can stimulate secretion from mast cells by directly activating G proteins that play a role in stimulus-secretion coupling. When internally applied, neomycin presumably stimulates secretion by activating a G protein that is located downstream to PLC. This G protein serves as a substrate for PtX.
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PMID:Neomycin is a potent secretagogue of mast cells that directly activates a GTP-binding protein involved in exocytosis. 170 86

We have examined the effects of sodium fluoride (NaF) on amylase release, cellular adenosine 3',5'-cyclic monophosphate (cAMP) level, inositol phosphate formation, and cytosolic free Ca2+ concentration ([Ca2+]i) in dispersed rat parotid acini or cells. At concentrations greater than 1 mM, NaF significantly increased amylase release. The maximum response was observed at 10 mM NaF and was comparable to that of the muscarinic-cholinergic agonist carbachol. Removal of extracellular Ca2+ with EGTA markedly suppressed the NaF-induced secretory response. At concentrations up to 10 mM, NaF did not increase the cellular level of cAMP, indicating that the NaF-induced amylase release is not mediated by cAMP. NaF (1-20 mM) caused a slow increase in [Ca2+]i in a concentration-dependent manner, as monitored with the fluorescent Ca2+ indicator fura-2, and the increased [Ca2+]i did not decline for at least 10 min after addition of NaF. In the absence of extracellular Ca2+, NaF evoked only a small and transient increase in [Ca2+]i. The addition of 10 mM NaF produced a significant accumulation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate. These results suggest that the NaF-induced amylase release is mediated by a breakdown of phosphoinositides leading to Ca2+ mobilization. The effects of fluoride may be through the action of F- on the GTP-binding protein(s) coupled to phospholipase C.
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PMID:NaF-induced amylase release from rat parotid cells is mediated by PI breakdown leading to Ca2+ mobilization. 170 96

Thrombin induced an increase in [Ca2+]i in mouse mastocytoma P-815 cells. This increase was markedly reduced by prior exposure to pertussis toxin (PT) but not by removal of extracellular Ca2+, suggesting that thrombin stimulates phospholipase C via a PT-sensitive GTP-binding protein. ATP also induced an increase in [Ca2+]i. This increase was insensitive to PT but completely suppressed on removal of extracellular Ca2+, suggesting that ATP stimulates Ca2+ influx in a PT-insensitive manner. Iloprost, a stable prostacyclin analogue, increased the cellular cAMP level and dose-dependently inhibited the thrombin-induced increase in [Ca2+]i, whereas the ATP-induced increase in [Ca2+]i was markedly enhanced by iloprost. Cyclic AMP analogues, dibutyryl cAMP and 8-bromo cAMP, also inhibited the increase in [Ca2+]i induced by thrombin and promoted that by ATP, indicating that the inhibitory and stimulatory effects of iloprost are mediated by cAMP. These results suggest that the prostacyclin receptor differentially regulates two distinct Ca2+ mobilizing systems via cAMP in mastocytoma cells.
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PMID:Differential regulation of thrombin- or ATP-induced mobilization of intracellular Ca2+ by prostacyclin receptor in mouse mastocytoma cells. 170 39

Dual inhibitory and stimulatory actions of guanine nucleotides on luteinizing-hormone (LH) exocytosis were observed in primary sheep gonadotropes permeabilized with staphylococcal alpha-toxin. At resting cytosolic [Ca2+]free (pCa 7), 5'-[gamma-thio]triphosphate (GTP[S]) and guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) stimulated rapid LH exocytosis, which was maximal between 5 and 10 min. GTP[S] and p[NH]ppG had similar potencies (50% of maximum effect at 20-50 microM), but the effect of p[NH]ppG was more prolonged. Experiments carried out in the presence of saturating concentrations of phorbol 12-myristate 13-acetate (PMA), or in PMA-desensitized cells, suggested that stimulation by p[NH]ppG is mediated by a mechanism additional to protein kinase C (PKC) activation. Furthermore, p[NH]ppG stimulated LH exocytosis in the presence of saturating cyclic AMP (cAMP) concentrations, although its effect was less than additive. However, when both PMA and cAMP were present, p[NH]ppG did not stimulate a further increase in the rate of LH exocytosis. In contrast, pretreatment of cells with GTP[S] at low [Ca2+]free markedly inhibited subsequent responses to Ca2+, cAMP, PMA, and cAMP plus PMA. This inhibitory effect required lower GTP[S] concentrations than the stimulatory effect (50% inhibition at 1-10 microM), and was not observed with p[NH]ppG. A similar inhibition was observed with adenosine 5'-[gamma-thio]triphosphate, probably by its conversion into GTP[S]. These results suggest that the stimulatory actions of guanine nucleotides can be accounted for by the combined activation of PKC and generation of cAMP, resulting from activation of conventional signal-transducing GTP-binding proteins. The inhibitory effect of GTP[S] can be clearly distinguished and indicates the involvement of a distinct GTP-binding protein in exocytosis at a site distal to second-messenger generation.
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PMID:Inhibition of luteinizing-hormone exocytosis by guanosine 5'-[gamma-thio]triphosphate reveals involvement of a GTP-binding protein distal to second-messenger generation. 170 5

Substance P (SP) stimulates polyphosphoinositide breakdown in the rat anterior pituitary through an NK-1 receptor. In the present study we present evidence that the coupling between the SP-NK1 receptor complex and polyphosphoinositide-specific phospholipase C (PI-PLC) in rat anterior pituitary membranes may involve a mechanism consistent with a GTP-binding protein. The formation of inositol phosphates from [3H]myo-inositol-labelled anterior pituitary membranes induced by SP was potentiated by GTP and non-hydrolysable guanine nucleotides. The stimulatory effects of SP alone and SP plus GTP could be blocked by addition of GDP-beta-S (guanosine 5-O-(thiodiphosphate] in excess. Basal and SP plus guanine nucleotide-induced inositol phosphate formation were stimulated by fluoride, whereas the effect of SP alone was inhibited. Pretreatment of anterior pituitary membranes with sodium deoxycholate attenuated the inositol phosphate response elicited by GTP and GTP-gamma-S, whereas basal and SP-stimulated inositol phosphate production showed a peak at 1 mg sodium deoxycholate/ml. SP, fluoride and guanine nucleotide stimulatory effects on hydrolysis of polyphosphoinositide (PPI) were unaffected by pretreatment of anterior pituitary cells with cholera or pertussis toxin for 12h. Treatment of anterior pituitary membranes with cholera and pertussis toxin yielded [32P]ADP-ribosylation of two proteins with molecular masses of 45 and 41 kDa respectively. We conclude that SP coupling to PI-PLC through the NK1 receptor in the rat anterior pituitary involves a GTP-binding mechanism distinct from the G-proteins associated with adenylate cyclase, Gs and Gi.
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PMID:Substance P stimulation of polyphosphoinositide hydrolysis in rat anterior pituitary membranes involves a GTP-dependent mechanism. 171 80

In a previous study, we have shown that freshly isolated glomerulosa cells possess dopamine (DA) receptors from both DA-1 and DA-2 subclasses, whereas in cultured conditions, cells exhibit dopamine receptors from the DA-1 subclass only. In the present work, we have studied the effect of DA on angiotensin-stimulated glomerulosa cells in these two experimental conditions. Our results demonstrate that in isolated cells, angiotensin II (AT) stimulates inositol phosphate accumulation, calcium influx and steroid secretion. Treatment with pertussis toxin completely blocks AT-stimulated steroid secretion and calcium influx and partially reduces inositol phosphate accumulation. DA alone has no effect on cAMP accumulation. However, in the presence of a specific DA-1 antagonist (SCH 23390), DA reduces intracellular cAMP content. Similarly, DA-like pertussis toxin produces the same inhibitory effects on AT-stimulated cells. The combined influence of DA and pertussis toxin is not additive suggesting that a 'Gi' GTP-binding protein is involved in the DA action. Specific DA antagonists indicate that these inhibitory processes are mediated through the DA-2 receptor subtype. DA may act by decreasing the intracellular calcium concentration since it reduces AT-stimulated Ca2+ influx and that both phospholipase C (PLC) and steroid accumulation are calcium dependent. Yet a direct inhibitory coupling between the DA-2 receptor and PLC may represent a second alternative since DA inhibitory effects are always present when calcium influx is artificially increased or decreased. In cultured cells, we observe an additive effect of DA and AT on aldosterone secretion, which is the result of additive interactions of the second messengers involved, namely cAMP for dopamine and inositol phosphates for angiotensin II. From these studies, we conclude that DA may exert a more versatile effect on aldosterone secretion than previously suspected.
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PMID:Mechanisms involved in the interaction of dopamine with angiotensin II on aldosterone secretion in isolated and cultured rat adrenal glomerulosa cells. 183 52

Long-term ethanol exposure is known to inhibit bradykinin-stimulated phosphoinositide hydrolysis in cultures of neuroblastoma x glioma 108-15 cells. In the present study, [3H]bradykinin binding, GTP-binding protein function, and phospholipase C activity were assayed in cells grown for 4 days in 100 mM ethanol with the aim of elucidating the molecular target of ethanol on signal transduction coupled to inositol trisphosphate and diacylglycerol formation. Ethanol exposure reduced guanosine 5'-O-(3-thiotriphosphate) [GTP(S)]- and, to a lesser extent, NaF/AlCl3-stimulated phosphoinositide hydrolysis, whereas it had no effect on the enzymatic activity of a phosphatidylinositol 4,5-bisphosphate-specific phospholipase C. [3H]Bradykinin binding in the absence of GTP(S) was not influenced by ethanol exposure. However, the reduction in [3H]bradykinin binding seen in control cells after addition of GTP analogue was inhibited in cells grown in ethanol-containing medium. The results indicate that long-term ethanol exposure exerts its effects on receptor-stimulated phosphoinositide hydrolysis primarily at the level of the GTP-binding protein.
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PMID:G proteins coupled to phospholipase C: molecular targets of long-term ethanol exposure. 185 Dec 10

The beta-subunit (G-beta) of the squid (Loligo forbesi) visual GTP-binding protein (G-protein), thought to be associated with a phosphatidylinositol-specific phospholipase C, has been identified and the sequence of the protein determined from its cDNA. The predicted polypeptide has a very marked sequence similarity with its mammalian counterparts (80-90% identity). Squid G-beta also has somewhat lower similarity to the yeast protein STE4 (approx. 40% identity). The role of G-beta in signal transduction is discussed in the light of its pronounced structural conservation.
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PMID:Sequence of the beta-subunit of the phosphatidylinositol-specific phospholipase C-directed GTP-binding protein from squid (Loligo forbesi) photoreceptors. 189 86

We have examined the influence of guanine nucleotides on Ca2(+)-dependent amylase secretion from SLO permeabilized rat pancreatic acini. GTP gamma S (100 microM) stimulated Ca2+ dependent amylase release, decreasing the EC50 for Ca2+ from 1.4 to 0.8 microM. By contrast, GDP (1mM) and dGDP (1mM) inhibited the maximal Ca2(+)-dependent secretory response. Measurement of IP3 liberation showed that Ca2+ stimulation did not increase the activity of phospholipase C (PLC) postulated to be linked to a G-protein termed Gp; GDP and dGDP must therefore be exerting their inhibitory action via a GTP-binding protein distinct from the PLC-linked Gp.
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PMID:Ca2(+)-dependent amylase secretion from pancreatic acinar cells occurs without activation of phospholipase C linked G-proteins. 189 67


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