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)

We have examined the cross talk between adenosine and bradykinin receptors in DDT1 MF-2 smooth muscle cells. Both adenosine and bradykinin mobilized intracellular free calcium via the formation of inositol 1,4,5-trisphosphate in a time- and dose-dependent manner. Adenosine exerted its actions via adenosine A1 receptors as demonstrated by the observations that N6-cyclopentyladenosine, a selective A1 receptor agonist, had an EC50 in the low nanomolar range and that a selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine, counteracted adenosine-mediated responses at concentrations typical for signaling via adenosine A1 receptors. Adenosine A1 receptors were coupled to phospholipase C via pertussis toxin-sensitive guanine nucleotide-binding regulatory protein(s) [G protein(s)], whereas bradykinin responses were unaffected by pertussis toxin. When adenosine or N6-cyclopentyladenosine was combined with bradykinin, the resulting formation of inositol 1,4,5-triphosphate was more than additive, and the EC50 value for adenosine and N6-cyclopentyladenosine was shifted to the left by bradykinin, the affinity of which was unaltered. Combining N6-cyclopentyladenosine and bradykinin also synergistically raised intracellular free calcium both at subthreshold levels and at maximal concentrations of the two agonists. The interaction was not dependent upon cAMP. In conclusion, stimulation of adenosine A1 receptors coupled to pertussis toxin-sensitive G protein(s) and bradykinin receptors coupled to pertussis toxin-insensitive G protein(s) synergistically mobilizes intracellular free calcium and inositol 1,4,5-trisphosphate formation.
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PMID:Stimulation of adenosine A1 receptors and bradykinin receptors, which act via different G proteins, synergistically raises inositol 1,4,5-trisphosphate and intracellular free calcium in DDT1 MF-2 smooth muscle cells. 132 31

High efficiency transient transfection of Cos-7 cells was previously used to establish the functional coupling between G alpha q/G alpha 11 and phospholipase C beta 1 (Wu, D., Lee, C-H., Rhee, S. G., and Simon, M. I. (1992) J. Biol. Chem. 267, 1811-1817). Here the same system was used to study the functional coupling between other guanine nucleotide-binding regulatory protein (G-protein) alpha subunits and phospholipases and to study which G alpha subunits mediate the activation of phospholipase C by the alpha 1-adrenergic receptor subtypes, alpha 1 A, alpha 1 B, and alpha 1 C. We found that G alpha 14 and G alpha 16 behaved like G alpha 11 or G alpha q, i.e. they could activate endogenous phospholipases in Cos-7 cells in the presence of AIFn. The synergistic increase in inositol phosphate release in Cos-7 cells after they were cotransfected with cDNAs encoding G alpha subunits and phospholipase C beta 1 indicates that both G alpha 16 and G alpha 14 can activate phospholipase C beta 1. The activation of phospholipase C beta 1 was restricted to members of the Gq subfamily of alpha subunits. They activated phospholipase C beta 1 but not phospholipase C gamma 1, gamma 2, or phospholipase C delta 3. The cotransfection of Cos-7 cells with cDNAs encoding three different alpha 1-adrenergic receptors and G alpha q or G alpha 11 leads to an increase in norepinephrine-dependent inositol phosphate release. This indicates that G alpha q or G alpha 11 can mediate the activation of phospholipase C by all three subtypes of alpha 1-adrenergic receptors. With the same assay system, G alpha 16 and G alpha 14 appear to be differentially involved in the activation of phospholipase C by the alpha 1-adrenergic receptors. The alpha 1 B subtype receptor gave a ligand-mediated synergistic response in the cells cotransfected with either G alpha 14 or G alpha 16. However, the alpha 1 C receptor responded in cells cotransfected with G alpha 14 but not G alpha 16, and the alpha 1 A receptor showed little synergistic response in cells transfected with either G alpha 14 or G alpha 16. The ability of the alpha 1 A and alpha 1 C receptors to activate phospholipase C through G alpha q and G alpha 11 was also demonstrated in a cell-free system.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activation of phospholipase C by alpha 1-adrenergic receptors is mediated by the alpha subunits of Gq family. 133 87

Epidermal growth factor (EGF) can stimulate inositol lipid hydrolysis in rat hepatocytes and can accelerate GTP/GDP exchange in hepatic membranes. Both of these responses can be abolished by pretreatment with pertussis toxin, suggesting that EGF may regulate phospholipase C (PLC) activity via a guanine nucleotide-binding regulatory protein (G protein) in liver cells. In contrast, in A431 human epidermoid carcinoma cells EGF can induce a rapid phosphorylation of PLC-gamma on tyrosine residues that increases the activity of immunoprecipitated PLC-gamma, suggesting that tyrosine phosphorylation of PLC-gamma may be the mechanism for EGF-stimulated inositol trisphosphate production in these cells. To determine the importance of the phosphorylation of PLC-gamma on tyrosine residues in a system where the EGF receptor apparently couples to a G protein, the effect of EGF on tyrosine phosphorylation of PLC-gamma was examined in rat hepatocytes. PLC-gamma was immunoprecipitated from cell lysates with a PLC-gamma antiserum and its tyrosine phosphorylation state was determined using both Western blot analysis with phosphotyrosine antibodies and direct measurement of phosphorylated amino acids. The results were compared with analogous experiments performed with A431 cells and another cultured cell line expressing high levels of human EGF receptors, Rat1hER fibroblasts. Although the amount of PLC-gamma in rat hepatocytes is similar to that in A431 cells and slightly higher than that in Rat1hER cells, EGF causes a barely detectable increase in the phosphorylation of PLC-gamma on tyrosine in hepatocytes, whereas it stimulates a significant degree of phosphorylation of PLC-gamma on tyrosine in Rat1hER or A431 cells. Pretreatment of hepatocytes with pertussis toxin abolishes the ability of EGF to activate PLC, as determined by an increase in intracellular Ca2+, but has no effect on the small amount of phosphate incorporated into tyrosine residues on the PLC-gamma protein, demonstrating that this low level of PLC-gamma phosphorylation does not correlate with changes in PLC activity. The data suggest that phosphorylation of PLC-gamma on tyrosine is not important for EGF-enhanced PLC activity in hepatocytes. This conclusion implies that EGF may use a mechanism to regulate PLC activity in hepatocytes that is different from that used in cultured cells expressing high levels of EGF receptors.
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PMID:Epidermal growth factor activates phospholipase C in rat hepatocytes via a different mechanism from that in A431 or rat1hER cells. 143 49

Recently, we have reported that the isolated guanine nucleotide-binding regulatory protein, Gh, couples to the alpha 1-adrenergic receptor (Im, M.-J., and Graham, R. M. (1990) J. Biol. Chem. 265, 18944-18951 and Im, M.-J., Riek, R.P., and Graham, R. M. (1990) J. Biol. Chem. 265, 18952-18960) and has a molecular mass of approximately 74 kDa, and the approximately 50-kDa protein which is copurified probably regulates guanine nucleotide binding of the 74-kDa GTP-binding protein. In this paper, we describe the role of purified Gh in the regulation of phospholipase C in the reconstitution system. The stimulation of phospholipase C activity by Gh effectively occurred at a low calcium concentration (less than or equal to 2 microM), but the phospholipase C (PLC) itself required at least 50-100 times more calcium to become fully activated. The characteristic nature of phospholipase C stimulation by Gh is its response to the calcium concentration. Thus, the enzyme activity changes in narrow submicromolar ranges and reaches maximal stimulation, but it does not extend to the levels above those stimulated by calcium alone. The calcium concentrations for the maximal stimulation of phospholipase C activity were 10-20 microM with phospholipid vesicles and 100-200 microM with detergent solution. These calcium concentrations were further decreased when Gh and phospholipase C were co-reconstituted into the phospholipid vesicles or in the detergent solution. The maximal stimulations of the PLC activity were reached at less than 5 microM calcium in both the vesicles and the detergent solution. The changes of calcium concentration for the activation of PLC are quite different from those obtained by reconstituting PLC-beta 1 with Gq-like G-proteins (Smarcka, A. V., Hepler, J. R., Brown, K. O., and Sternweis, P. C. (1991) Science 251, 804-807 and Taylor, S. J., Chae, H. Z., Rhee, S. G., and Exton, J. H. (1991) Nature 350, 516-518). The phospholipase C activity was stimulated in a Gh concentration-dependent manner in the presence of GTP gamma S. The phospholipase C activity was activated by Gh alpha in the presence of aluminum fluoride, but not by Gh beta. Furthermore, a Gh.PLC complex can be induced by incubation with aluminum fluoride in a detergent solution and partially purified without the dissociation of related proteins. Thus, our reconstitution studies show that the pattern of stimulation of PLC by AIF-4-activated Gh in the ternary complex is similar to the stimulation of PLC activated by Gh in both detergent solution and phospholipid vesicles.
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PMID:Characterization of a phospholipase C activity regulated by the purified Gh in reconstitution systems. 157 27

The cloned 5-HT1A receptor, stably expressed in HeLa cells, has been shown to mediate the effects of 5-hydroxytryptamine (5-HT) to inhibit cAMP formation and to stimulate the hydrolysis of phosphatidylinositol. Both responses were found to be pertussis toxin sensitive. We have examined these two responses in membranes derived from these cells and show that the 5-HT1A receptor can directly regulate the activity of adenylyl cyclase and phospholipase C in response to agonist. In order to examine whether the same or distinct guanine nucleotide-binding regulatory protein(s) (G protein) are involved in these two signal transduction pathways, we used anti-peptide antibodies recognizing the alpha-subunits of Gi1, Gi2, Gi3 as specific tools, since these pertussis toxin substrates are expressed in HeLa cells. These antibodies have previously been shown to prevent receptor-G protein coupling by binding to the regions of G proteins which are putatively involved in interaction with receptors. Our results indicate that the Gi proteins, but preferentially Gi3, mediate the effects of 5-HT both to inhibit adenylyl cyclase and to stimulate phospholipase C. These findings demonstrate that the same receptor interacting with the same G protein can regulate several distinct effector molecules.
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PMID:Dual coupling of the cloned 5-HT1A receptor to both adenylyl cyclase and phospholipase C is mediated via the same Gi protein. 178 5

Extracellular ATP and UTP produced a rapid accumulation of inositol phosphates in human airway epithelial cells (CF/T43). The order of agonist potencies for a series of nucleotide analogues differed markedly from that of the classically described P2x- or P2y-purinergic receptors. UTP was the most potent agonist and was fully efficacious; ATP and adenosine-5'-O-(3-thiotriphosphate) were also full agonists. In contrast, 2-methylthio-ATP, adenosine-5'-O-(2-thiodiphosphate) and alpha,beta-methylene-ATP were without effect. ADP and UDP had little or no effect at concentrations as high as 100 microM, and deoxyribose and dideoxyribose compounds were inactive. The effects of ATP and UTP were not additive, whereas bradykinin- or histamine-stimulated inositol phosphate production was additive with the effects of ATP or UTP. Preincubation of cells with either UTP or ATP resulted in a parallel loss of responsiveness to both agonists. Desensitization was specific for the response to nucleotides, because no ATP- or UTP-induced effect on the response to histamine or bradykinin was observed. Pertussis toxin treatment of CF/T43 cells produced a 30-40% decrease in the response to ATP or UTP, which correlated with the ADP-ribosylation of 41- and 43-kDa proteins. Bradykinin and histamine responses were not modified by pertussis toxin. Guanine nucleotides had little effect on the inositol phosphate response in intact CF/T43 cells at concentrations below 100 microM. However, in streptolysin-O-permeabilized cells GTP-gamma S produced a concentration-dependence activation of inositol phosphate formation. UTP or ATP had little effect in permeabilized cells in the absence of guanine nucleotides but markedly increased inositol phosphate formation in the presence of guanine nucleotides. Taken together, these results suggest that UTP and ATP activate a 5'-nucleotide receptor on CF/T43 cells that is distinct from the classically defined P2x- and P2y-purinergic receptors. Activation of phospholipase C by this receptor involves, at least in part, a guanine nucleotide-binding regulatory protein.
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PMID:Evidence that UTP and ATP regulate phospholipase C through a common extracellular 5'-nucleotide receptor in human airway epithelial cells. 194 36

The parathyroid hormone (PTH) receptor is coupled via a guanine nucleotide-binding regulatory protein (G protein) to phospholipase C (PLC). Binding of PTH to its receptor leads to activation of PLC with the subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 generation leads to the release of intracellular calcium stores, which produces an increase in the intracellular calcium concentration. DAG activates protein kinase C (PKC). Both IP3 metabolites and PKC may play a role in returning the intracellular calcium concentration back to base line, by stimulating the movement of calcium from the intracellular to the extracellular compartment, as well as by sequestering calcium within intracellular organelles. PKC appears to be important in the development of desensitization and downregulation of the PTH receptor to PTH. Activation of PLC may be important in modulating the well-known effects of PTH on bone and kidney and also may be relevant to recently described actions, such as the possible role of PTH as a growth factor in skeletal tissue. Important issues that need to be addressed in this field include 1) characterization of the PTH receptor, 2) the possible role of low-molecular-weight G proteins in PTH signal transduction, and 3) further description of the role of alternate pathway signal transduction in producing the effects of PTH.
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PMID:PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney. 215 34

The mechanisms of endothelin-1 (ET) actions were investigated in cultured rat aortic vascular smooth muscle A-10 cells. The A-10 cells have a single class of high affinity binding sites for ET with an apparent Mr of 65,000-75,000 on SDS-PAGE. Stimulation of cells with ET induces mobilization of Ca2+ from both intra- and extracellular pools to produce a biphasic increase in cytoplasmic free Ca2+ concentration. ET increases cellular levels of inositol trisphosphate and 1,2-diacylglycerol, indicating activation of phospholipase C by ET. ET stimulates production of inositol phosphates in membranes prepared from A-10 cells in the presence of guanosine 5'-O-(thiotriphosphate) (GTP gamma S), but not in its absence. Further, specific binding of 125I-labeled ET to A-10 cell membranes is shown to be inhibited by GTP gamma S in a dose-dependent manner. Treatment of A-10 cells with pertussis toxin induces ADP-ribosylation of a 41,000-D membrane protein but fails to block the ET-induced increases in inositol phosphate production and Ca2+ mobilization. These results indicate that the receptor for ET is coupled to phospholipase C via a guanine nucleotide-binding regulatory protein which is distinct from the pertussis toxin substrate in A-10 cells.
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PMID:Endothelin receptor is coupled to phospholipase C via a pertussis toxin-insensitive guanine nucleotide-binding regulatory protein in vascular smooth muscle cells. 215 22

Treatment of a variety of cells and tissues with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C (PKC) results in the inhibition of receptor-coupled inositol phospholipid-specific phospholipase C (PLC) activity. To determine whether or not the targets of TPA-activated PKC include one or more isozymes of PLC, studies were carried out with PC12, C6Bu1, and NIH 3T3 cells, which contain at least three PLC isozymes, PLC-beta, PLC-gamma, and PLC-delta. Treatment of the cells with TPA stimulated the phosphorylation of serine residues in PLC-beta, but the phosphorylation state of PLC-gamma and PLC-delta was not changed significantly. Phosphorylation of bovine brain PLC-beta by PKC in vitro resulted in a stoichiometric incorporation of phosphate at serine 887, without any concomitant effect on PLC-beta activity. We propose, therefore, that rather than having a direct effect on enzyme activity, the phosphorylation of PLC-beta by PKC may alter its interaction with a putative guanine nucleotide-binding regulatory protein and thereby prevent its activation.
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PMID:Feedback regulation of phospholipase C-beta by protein kinase C. 221 70

Bone marrow-derived mouse mast cells were sensitized with monoclonal mouse IgE antibody and treated with cholera toxin (CT), which ADP-ribosylated the alpha-subunit of the stimulatory guanine nucleotide-binding regulatory protein Gs, prior to challenge with either antigen or thrombin. The CT treatment increased intracellular cAMP levels, but neither enhanced nor inhibited antigen-induced histamine release or arachidonate release. The same treatment of the sensitized bone marrow-derived mouse mast cells with CT markedly enhanced thrombin-induced histamine release without affecting arachidonate release. The CT treatment failed to affect antigen-induced and thrombin-induced generation of inositol trisphosphate and of diacylglycerol or mobilization of intracellular Ca2+. The results indicate that Gs in bone marrow-derived mouse mast cells is not involved in the transduction of the antigen-induced or thrombin-induced triggering signal to phospholipase C, which initiates the enhancement of phosphatidylinositol turnover. The enhancement of thrombin-induced histamine release by CT treatment with the observations that thrombin-induced histamine release was inhibited by pretreatment of the cells with pertussis toxin suggest that the involvement of a guanine nucleotide-binding regulatory protein in thrombin-induced biochemical events is an event distal to Ca2+ mobilization.
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PMID:Effect of cholera toxin on histamine release from bone marrow-derived mouse mast cells. 245 25


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