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 mechanisms of stimulation of phospholipase C (PLC) by endothelin, specifically the role of guanine nucleotide-binding proteins (GTP-binding proteins) in coupling the endothelin receptor to PLC, were investigated in rat mesangial cells. Endothelin-1 (ET) synergistically released inositol polyphosphates in the presence of the stimulatory GTP analogue guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) in permeabilized cells. In addition, in intact cells, pertussis toxin partially inhibited the stimulation of total inositol phosphates (IPn) by ET. Pertussis toxin also reduced the peak ET-stimulated intracellular free calcium level ([Ca2+]i) in these cells, both in the presence and absence of extracellular calcium. Pertussis toxin induced ADP ribosylation of a 41- to 43-kDa protein in mesangial cell membranes, and this effect was inhibited by prior exposure to ET and augmented by the inhibitory GDP analogue, guanosine 5'-O-(2-thiodiphosphate) (GDP beta S). Thus a pertussis toxin-sensitive GTP-binding protein is involved in the activation of PLC by ET in glomerular mesangial cells.
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PMID:A pertussis toxin-sensitive GTP-binding protein couples endothelin to phospholipase C in rat mesangial cells. 190 Mar 89

In GH4C1 rat pituitary cells, a GTP-binding protein appears to be involved in signal transduction between the TRH receptor and phospholipase C. In certain other cell types, another role for GTP has been reported, namely regulation of Ca2+ translocation from one intracellular pool to another. Using digitonin-permeabilized GH4C1 cells, we have investigated whether an analogous process occurs in pituitary cells. In permeabilized GH4C1 cells, TRH, inositol 1,4,5-trisphosphate (IP3), and nonhydrolyzable GTP analogs guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and 5'-guanylyl imidodiphosphate each increased free Ca2+ concentration [( Ca2+]). Unlike several other systems, GTP did not increase [Ca2+]. Guanosine 5'-O-(2-thiodiphosphate) inhibited Ca2+ release induced by both TRH and GTP gamma S. Heparin abolished IP3-induced Ca2+ release but did not prevent Ca2+ release induced by TRH or GTP gamma S, suggesting a mechanism for their actions that did not depend solely on IP3 production. Neomycin inhibited GTP gamma S-induced Ca2+ release, but it did not prevent TRH- or IP3-induced Ca2+ release. In the absence of ATP, GTP gamma S did not elevate [Ca2+], although TRH and IP3 did, suggesting that ATP-dependent sequestration of Ca2+ was necessary for the action of GTP gamma S in this system, but not for TRH and IP3. Repeated additions of IP3 resulted in an attenuation of the response to IP3- GTP gamma S, which itself increased [Ca2+] after IP3 attenuation, restored the attenuated Ca2+ response to IP3. We conclude that, in permeabilized GH4C1 cells, GTP gamma S as well as TRH cause intracellular Ca2+ release; however, their mechanisms of action are, at least in part, distinct. Furthermore, the IP3-depletable Ca2+ pool can be refilled from a GTP gamma S-sensitive compartment via Ca2+ transport through the cytosol.
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PMID:Control of intracellular calcium redistribution by guanine nucleotides and inositol 1,4,5-trisphosphate in permeabilized GH4C1 cells. 190 95

We have studied the possible involvement of the GTP-binding protein (G-protein) in the activation of phospholipase C and A2 in cultured rat luteal cells as a transducer of cell information. 1. Inositol phosphate production and arachidonic acid release in rat luteal cells by the stimulation of PGF2 alpha and GnRH receptors are dependent on GTP and therefore suggest the involvement of GTP binding protein. 2. When the cells were not treated with IAP, a membrane protein of 41K molecular weight was apparently labeled. The protein, with a molecular weight of 41K, which was obtained from cultured rat luteal cells without prior treatment with IAP is considered to be the alpha-subunit of GTP binding protein as reported in other cells. While alpha-subunit of G-protein was ADP-ribosylated in luteal cells too, the 41K protein from the cells pretreated with IAP was not found to be ADP ribosylated. 3. When such IAP pretreated luteal cells were stimulated by PGF2 alpha or GnRHa, the production of inositol phosphate and the release of arachidonic acid were observed with no suppression. 4. The results suggest the existence of some G-protein other than Gi between the receptor and phospholipases C and A2.
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PMID:[A study on GTP-binding protein in the activation of phospholipase C and phospholipase A2 in cultured rat luteal cells]. 190 81

Upon engagement of chemoattractant receptors, neutrophils generate inositol trisphosphate and diacylglycerol (DG) by means of a phosphatidylinositol-specific phospholipase C (PI-PLC) which is regulated by a GTP-binding protein(s). We have previously reported (Reibman, J., H. M. Korchak, L. B. Vosshall, K. A. Haines, A. M. Rich, and G. Weissmann. 1988. J. Biol. Chem. 263:6322-6328) a biphasic rise in DG after exposure of neutrophils to the chemoattractant FMLP: a rapid (less than or equal to 15 s) phase ("triggering") and a slow (greater than or equal to 30 s) phase ("activation"). These derive from distinct intracellular lipid pools. To study the source of rapid and slow DG, we have used a unique probe, protein I, a porin that is the major outer membrane protein of Neisseria gonorrhoeae. Treatment of neutrophils with protein I inhibits exocytosis and homotypic cell adhesion provoked by FMLP without inhibiting assembly of the NADPH oxidase responsible for O2-. generation. DG turnover in PMN labeled with [3H]arachidonate and [14C]glycerol was profoundly altered by protein I. Whereas the rapid peak of DG was only modestly diminished (FMLP vs. FMLP plus protein I = DG labeled with [3H]arachidonic acid (3H-a.a.-DG): 142 +/- 14% SEM vs. 125 +/- 22%; DG labeled with the glycerol backbone with [14C]glycerol (D-14C-G): 125 +/- 10% SEM vs. 107 +/- 8.5% SEM), the slow rise in both 3H-a.a.-DG and D-14C-G was essentially abolished. Moreover, treatment of neutrophils with 4-4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), which, like protein I, inhibits exocytosis without affecting O2-. generation also inhibited slow DG. However, protein phosphorylation and dephosphorylation (47phox, 66phox) were unaffected in the absence of slow DG. To determine the source of the slow DG, we have analyzed radiolabeled phospholipid (PL) turnover after FMLP +/- protein I (P.I.). Treatment of PMN with FMLP (0.1 microM) resulted in breakdown of phosphatidylcholine (PC), beginning at 30 s, and reaching a nadir at 60 s (3H-PC = 59 +/- 10.2% SEM of resting, 14C-PC = 57 +/- 6.4%). Protein I (0.25 microM) significantly inhibited PC turnover after FMLP ([3H]PC = 95 +/- 5.6% and [14C]PC = 86 +/- 8.4% of resting at 60 s), but failed to alter the metabolism of 3H- or 14C-phosphatidylinositol after FMLP (91 +/- 19.6 and 88 +/- 16.5% vs. 92 +/- 9.2 and 91 +/- 16% at 60 s).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of protein I of Neisseria gonorrhoeae on neutrophil activation: generation of diacylglycerol from phosphatidylcholine via a specific phospholipase C is associated with exocytosis. 190 86

1. The fungal metabolite, wortmannin, has recently been shown to inhibit fMet-Leu-Phe-stimulated superoxide production and phospholipase D (PLD) activation in the human neutrophil. 2. We have found that a close structural analogue of wortmannin, demethoxyviridin, has a similar inhibitory profile but in addition blocks phosphatidylinositol 4,5-bisphosphate-specific phospholipase C and hence inositol 1,4,5-trisphosphate (IP3) formation. 3. Inhibition of fMet-Leu-Phe-stimulated PLD by demethoxyviridin was characteristically non-competitive (IC50 = 31 +/- 10 nM). 4. Inhibition of fMet-Leu-Phe-stimulation IP3 formation required concentrations almost 10 times higher (IC50 = 250 +/- 130 nM). 5. Surprisingly, demethoxyviridin only inhibited fMet-Leu-Phe-induced intracellular calcium mobilization at concentrations 100 times greater than those needed to block IP3 formation. 6. Demethoxyviridin also inhibited PLD activation induced by sodium fluoride or phorbol myristate acetate (PMA) but the concentrations required were 100 times those needed to block fMet-Leu-Phe-stimulated PLD. 7. These observations support the contention that PLD plays an important role in signal transduction in the human neutrophil and indicate that wortmannin and demethoxyviridin inhibit PLD activation at a common step in the signalling pathway. 8. Furthermore, these results suggest that demethoxyviridin may block the interaction between the chemotactic peptide receptor and a GTP-binding protein that is intimately involved in PLD activation.
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PMID:Demethoxyviridin and wortmannin block phospholipase C and D activation in the human neutrophil. 190 35

Both micromolar Ca2+ and guanosine 5'-[gamma-thio]triphosphate (GTP[S]) stimulated the formation of inositol phosphates (InsPs) in digitonin-permeabilized chromaffin cells prelabelled with [3H]inositol. The production of InsPs was potentiated by ATP. Guanosine 5'-[beta-thio]diphosphate (GDP[S]) caused a GTP-reversible shift to higher concentrations in the Ca(2+)-concentration-response curve for the release of InsPs without changing the maximal response. GTP[S] caused a shift to lower concentrations of Ca2+ and also increased the maximal response. The effects of GTP[S] and Ca2+ were synergistic. Although as much as 80% of the InsPs were derived from phosphatidylinositol 4-phosphate (PtdInsP) or 4,5-bisphosphate (PtdInsP2), the amount of InsPs produced could be several times the total amount of PtdInsP and PtdInsP2 in the cells and was largely accounted for by a decrease in PtdIns. The levels of labelled PtdInsP and PtdInsP2 increased on stimulation with Ca2+, but decreased on stimulation with GTP[S] or the combination of Ca2+ and GTP[S]. Preincubation with Ca2+ and ATP amplified the subsequent GTP[S]-induced production of InsPs. ATP and its gamma-thio and beta gamma-imido analogues stimulated the formation of InsPs in intact cells. However, only ATP potentiated the responses to Ca2+ and GTP[S] in permeable cells. Our main conclusions are: (1) a GTP-binding protein participates in the Ca(2+)-induced production of InsPs by phospholipase C, and (2) ATP markedly potentiates the stimulated formation of InsPs, an effect with arises from its role in polyphosphoinositide synthesis and does not involve purinergic receptor activation in permeabilized cells. The data also suggest that the different effects of Ca2+ and GTP[S] on polyphosphoinositide synthesis probably contribute to the synergistic action of Ca2+ and GTP[S] on the generation of InsPs.
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PMID:Regulation of the formation of inositol phosphates by calcium, guanine nucleotides and ATP in digitonin-permeabilized bovine adrenal chromaffin cells. 195 41

ADP-ribosyltransferase from Clostridium botulinum type C strain was found to induce an increase of inositol phosphates (IPs) formation in murine thymocytes membranes. Incubation of electropermeabilized murine thymocytes with the enzyme also caused an increase of IPs formation in the cells. This increase of IPs formation in the enzyme-treated membranes and electropermeabilized cells was dependent on the amount of both NAD and the enzyme, suggesting that the stimulation of phosphoinositide-specific phospholipase C (PLC) was related to ADP-ribosylation of membrane proteins by the enzyme. On the other hand, in calf and murine thymocytes two proteins with the same molecular weight of 21,000 were found to be ADP-ribosylated by the botulinum ADP-ribosyltransferase. A minor ADP-ribosylation substrate was shown by two-dimensional polyacrylamide gel electrophoresis to be G21k, a low-molecular-weight GTP-binding protein (G protein) suggested previously by us to be involved in PLC regulation [Wang, P. et al. (1987) J. Biochem. 102, 1275-1287; (1988) 103, 137-142; and (1989) 105, 461-466], and the other major ADP-ribosylation substrate was identified as a rho A protein. Under the experimental conditions of the IPs formation study, ADP-ribosylation of both G21k and rho A proteins by botulinum ADP-ribosyltransferase in membranes and permeabilized cells was observed. These results suggest that botulinum ADP-ribosyltransferase-induced PLC stimulation in thymocytes is closely correlated with ADP-ribosylation of the low-molecular-weight G proteins.
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PMID:Low-molecular-weight GTP-binding proteins serving as ADP-ribosylation substrate for ADP-ribosyltransferase from Clostridium botulinum and their relation to phosphoinositides metabolism in thymocytes. 196 61

The effect of the vasodilatory peptide bradykinin on the regulation of phosphoinositide metabolism in endothelial cells was investigated. Activation of phosphoinositide metabolism by bradykinin in the endothelium of the bovine pulmonary artery was not blocked by pertussis toxin, which ADP-ribosylates a membrane protein of molecular mass 40 kDa, but botulinum toxin, which ADP-ribosylates a membrane protein of molecular mass 24 kDa, fully blocked bradykinin-stimulated phosphoinositide metabolism. The effect of bradykinin was potentiated by guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), an activator of GTP-binding proteins, and inhibited by guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S), an inhibitor of GTP-binding proteins. Activation of phosphoinositide metabolism by bradykinin was fully blocked by a B2-receptor antagonist, whereas a B1-receptor antagonist did not affect bradykinin action. It is concluded that the B2-receptor in endothelial cells is coupled to phospholipase C via a GTP-binding protein, which is a substrate for botulinum toxin.
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PMID:Regulation by bradykinin of phosphoinositide metabolism in the endothelial cells of the pulmonary artery. 196 71

Synergism between 0.5 mM inositol and cytokinin in the stimulation of plant tissue culture growth suggests a role for inositol in the mediation of cytokinin action. Investigation of the effects of cytokinin on the pattern of labelling of lipids from radioactive precursors by cytokinin-responsive cells of a cytokinin-dependent soybean cell suspension culture did not detect any reproducible link between cytokinin action and lipid labelling after 10 min. Evidence for links between auxin action and phosphoinositide metabolism in other systems would benefit from confirmation of long term repeatability and more rigorous chemical characterization of the compounds involved. For plant growth substance action to be mediated by release of inositol trisphosphate from phosphatidylinositol bisphosphate, activation of phospholipase C, possibly requiring potentiation by a GTP-binding protein, would be expected. Reports of G-protein effects on plant phospholipase C activity are conflicting. There is evidence for G-protein stimulation of activity from the results of assays using endogenous substrates, although the products released have not been fully characterized. Other results, from assays using exogenous substrates, have shown no effect of GTP analogues on the enzymic breakdown of phosphatidylinositol bisphosphate. Using endogenously labelled membranes from soybean cells, we were unable to detect effects attributable to G-protein potentiation. None of a range of growth substances at physiologically active concentrations proved able to alter detectably the lack of response of polyphosphoinositidase activity to GTP-analogues. The activity was, however, strongly stimulated by Ca2+ at micromolar levels, a characteristic widely reported. In consequence, the possibility that transient increases in the labelling of inositol phosphate fractions may be a result of increases in cytosolic Ca2+ levels needs to be addressed. If there is a role for inositol in soybean cell activation by cytokinin, we have no evidence that it involves polyphosphoinositide cleavage. That there is a special role for inositol in the mitotic cycle of soybean cells and in addition to the maintenance of viability is shown by the results of experiments in which endogenous inositol synthesis was inhibited. Further research aims to identify the inositol-requiring steps and their relationship, if any, with the auxin-requiring and cytokinin-requiring steps in the mitotic cycle of cultured soybean cells.
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PMID:Phosphoinositides and plant growth substance action. 196 35

Rat adipose cells treated with Staphylococcus aureus alpha-toxin are permeable and retain their ability to respond to insulin after hormone treatment. The GLUT 4 glucose transporter isoform, specific to fat and muscle cells, is translocated normally from low density microsomes to the plasma membrane in permeabilized cells. Addition of guanosine 5'-O-(3-thiotriphosphate), guanylyl imidodiphosphate, or guanylyl beta, gamma-methylenediphosphate to permeabilized adipocytes induces an insulin-like translocation of GLUT 4 to the plasma membrane; GTP or adenosine 5'-(beta, gamma-imino)triphosphate has no effect. No translocation of GLUT 4 is observed when GTP analogs are added to intact adipocytes. These results suggest the involvement of a GTP-binding protein in insulin-triggered recruitment of GLUT 4 to the cell surface.
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PMID:Insulin and nonhydrolyzable GTP analogs induce translocation of GLUT 4 to the plasma membrane in alpha-toxin-permeabilized rat adipose cells. 199


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