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 neuroblastoma line SK-N-SH consists of distinct and interconverting cell types, which include a neuroblast phenotype (SH-SY5Y), an epithelial phenotype (SH-EP), and an intermediate cell type (SH-IN). In SH-SY5Y cells, only muscarinic receptor activation produced stimulation of phosphoinositide turnover, whereas in SH-EP cells, where muscarinic receptors are not present, the peptides bradykinin, endothelin, and angiotensin II stimulated phosphoinositide hydrolysis with EC50 values of 16, 6, and 0.7 nM, respectively, and a rank order of maximal effects of bradykinin greater than endothelin greater than angiotensin II. Fetal calf serum at concentrations between 1 and 10% was also a potent stimulator of phosphoinositide hydrolysis in SH-EP cells but not in SH-SY5Y cells. In the intermediate cell clone, SH-IN, phosphoinositide hydrolysis was stimulated not only by muscarinic receptors, but also by endothelin, bradykinin, and serum, an indication that this cell type harbors all the kinds of receptors that are differentially expressed in the other two cell types. The effects of the three peptides--bradykinin, endothelin, and angiotensin II--on phosphoinositide hydrolysis in SH-EP cells were additive, a result suggesting that the three kinds of receptors may activate distinct transducer proteins and/or phospholipase C subtypes. Pretreatment of intact SH-EP cells with pertussis toxin under conditions sufficient to ADP-ribosylate 90-95% of the endogenous guanine nucleotide regulatory protein substrates did not impair the ability of any of the receptors to stimulate phosphoinositide hydrolysis in any of the cell types. In contrast, short-term exposure to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (1 microM) abolished the stimulation of phosphoinositide hydrolysis mediated by peptide receptors in SH-EP cells and partially inhibited that by muscarinic receptors in SH-SY5Y cells. Prolonged incubation of SH-EP cells with phorbol ester resulted in a recovery of receptor responsiveness, the extent and rate of which were different for each receptor type. In contrast, there was no recovery of responsiveness for muscarinic receptors in SH-SY5Y cells. The pattern of phorbol ester-mediated effects depended on the cell rather than on the receptor type. In fact, muscarinic receptor responsiveness in SH-IN, the intermediate cell type, was desensitized by and recovered from treatment with phorbol esters in a manner more similar to peptide receptors in SH-EP than to muscarinic receptors in SH-SY5Y. These data suggest that the transduction mechanisms by which distinct receptor types are coupled to phosphoinositide hydrolysis in the three cell phenotypes differ in sensitivity to feedback regulation by protein kinase C.
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PMID:The epithelial phenotype of human neuroblastoma cells express bradykinin, endothelin, and angiotensin II receptors that stimulate phosphoinositide hydrolysis. 130 39

Activation of phosphoinositide-specific phospholipase C (PLC) generates two intracellular signals which play major roles in many cellular processes including secretion, proliferation and contraction. PLC activation by many receptors occurs via a guanine nucleotide regulatory protein, Gp. PLCs are found predominantly in the cytosolic fraction though some activity is membrane-associated. At least four families of iso-enzymes of PLC (alpha, beta, gamma and delta) have been identified, but there is only scant evidence to indicate that any of the mammalian cytosolic activities are involved in G-protein-regulated signalling. In this study we demonstrate that the PLC activity from rat brain cytosol can be regulated in a G-protein-dependent manner in a reconstituted system using pre-permeabilized HL60 cells. We identify two enzymes, PLC-beta and a novel 86 kDa enzyme (designated PLC-epsilon) as the G-protein-regulated enzymes. PLC-epsilon was found to be the major G-protein-regulated enzyme.
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PMID:Identification of a novel cytosolic poly-phosphoinositide-specific phospholipase C (PLC-86) as the major G-protein-regulated enzyme. 165 Dec 29

We explored the nature and time course of the multiple signal transduction pathways for V1-vascular vasopressin (AVP) receptors of A7r5 aortic smooth muscle cells in culture by using radioligand binding techniques, intracellular calcium monitoring, and polyphosphoinositide and phospholipid analyses. V1-vascular AVP receptors of A7r5 cells were characterized by the agonist radioligand [3H]AVP and the antagonist radioligand [3H]d(CH2)5Tyr(Me)AVP. Affinity and capacity of agonist but not antagonist binding were modulated by MgCl2 and aluminum fluoride, suggesting that the receptors are coupled to a guanine nucleotide regulatory protein. In fura-2-loaded A7r5 cells, AVP induced within seconds a dose-dependent increase of free intracellular Ca++ ([Ca++]i) consisting of a rapid transient spike and a sustained increase lasting for 3-5 min. The baseline [Ca++]i was 136 +/- 18 nM, the maximum [Ca++]i response to AVP was 1,582 +/- 297 nM, and AVP ED50 was 1.87 +/- 0.15 nM. Diverse experiments performed with EGTA, 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethylester, Mn++, ionomycin, terbutylbenzo hydroquinone, and nicardipine suggested that the initial spike resulted from both intracellular Ca++ release from the endoplasmic reticulum and extracellular Ca++ influx, whereas the sustained phase depended on dihydropyridine-insensitive extracellular Ca++ influx. Experiments done with indomethacin and arachidonic acid indicated that AVP-induced extracellular Ca++ influx was in part dependent on phospholipase A2 activation. In [3H]myoinositol and [3H]arachidonate-labeled A7r5 cells, AVP stimulated inositol 1,4,5 trisphosphate and 1,2 diacylglycerol production via activation of phospholipase C. Also, AVP stimulated a transphosphatidylation reaction through activation of phospholipase D in A7r5 cells labeled with [3H]1-O-alkyl lysoglycerophosphocholine. Thus, the stimulation of V1-vascular AVP receptors of A7r5 cells triggers several signaling pathways. The immediate and transient [Ca++]i rise due to mobilization of intracellular and extracellular Ca++ is associated with the activation of phospholipases A2 and C, and the sustained activation of phospholipase D.
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PMID:Multiple signaling pathways of V1-vascular vasopressin receptors of A7r5 cells. 165 17

Retinoic acid, a derivative of vitamin A, is shown to inhibit the levels of inositol phosphates and diacylglycerol by 25-30% when added to intact HL-60 cells at concentrations which induce differentiation. The onset of inhibition occurs after 10 min and reaches a maximum at 45 min. To study the mechanism and the site of action of retinoic acid, the activity of the phosphatidylinositol bisphosphate-specific phospholipase C was studied in cells permeabilized with streptolysin O and in membrane preparations. Phospholipase C activity was stimulated either via the guanine nucleotide regulatory protein (G-protein) or directly by Ca2+. Retinoic acid treatment, in a time- and concentration-dependent manner, led to a decrease in phospholipase C activity when stimulated with either GTP gamma S or NaF, both of which activate the enzyme via the G-protein. By contrast, it had no effect on the enzyme activity when stimulated with Ca2+ alone. This indicates that retinoic acid interferes with the coupling of the G-protein and phospholipase C. A relationship between the inhibition of phospholipase C activity and the induction of differentiation by retinoic acid was investigated. Only a small inhibition of GTP gamma S-stimulated phospholipase C activity was observed when an analogue of retinoic acid, etretine or Ro10-1670, with low differentiating activity, was used. Moreover, no inhibition of the GTP gamma S-stimulated phospholipase C activity was observed in an HL-60 sub-line resistant to retinoic acid. These results suggest that phospholipase C inhibition is an important step in the induction of differentiation.
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PMID:The differentiating agent, retinoic acid, causes an early inhibition of inositol lipid-specific phospholipase C activity in HL-60 cells. 190 36

Phospholipase C (specific for inositol lipids) is known to be present both in membranes and cytosol. Receptor-mediated activation of this enzyme occurs via a guanine nucleotide regulatory protein (G-protein), designated Gp. We have compared the stimulation of this enzyme by fMet-Leu-Phe via the G-protein in HL60 membranes and in permeabilised cells. fMet-Leu-Phe stimulated phospholipase C in membranes at 2 min and the response was dependent on exogenously added GTP. GTP alone also stimulated phospholipase C activity such that at 10 min the response to fMet-Leu-Phe was minimal. In comparison, the response to fMet-Leu-Phe in permeabilised cells was greater in extent but did not require added GTP. However, it was antagonized by GDP analogues (GDP[beta S] greater than GDP greater than dGDP) and by pertussis toxin pretreatment, indicating that fMet-Leu-Phe-stimulated phospholipase C activity was also mediated via Gp. GTP and its analogue GTP[gamma S] also stimulated phospholipase C and their effects were strictly additive to the stimulation obtained with fMet-Leu-Phe. Such additivity was also observed when two receptor-directed agonists, fMet-Leu-Phe and ATP, were used to stimulate intact cells. It is concluded that (a) the size of the response with fMet-Leu-Phe in membranes is limited by the loss of a component, possibly phospholipase C, and (b) stoichiometry and physical organisation of multiple species of G-proteins and/or phospholipases C may explain the independent nature of phospholipase C activation by fMet-Leu-Phe, ATP and guanine nucleotides.
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PMID:Characterization of fMet-Leu-Phe-stimulated phospholipase C in streptolysin-O-permeabilised cells. 201 14

In order to clarify the mechanism(s) by which cyclic GMP inhibits the generation of inositol phosphates in rat aorta segments and cultured bovine aortic smooth muscle cells, we studied phosphoinositide hydrolysis and GTPase activity in homogenates and membrane preparations of cultured bovine aortic smooth muscle cells. Pretreatment of homogenate preparations with cyclic GMP plus ATP did not inhibit [8-arginine, 3H] vasopressin (AVP) binding, but resulted in a total suppression of the AVP-induced GTPase activation. The pretreatment with cyclic GMP and ATP also inhibited the formation of inositol phosphates induced by AVP in the presence of low concentrations of guanosine 5'-(gamma-thio)triphosphate (GTP gamma S), or by high concentrations of GTP gamma S alone. However, the formation of inositol phosphates by high concentrations of Ca2+ alone was not blocked. These results suggest that the ability of cyclic GMP to inhibit phosphoinositide hydrolysis results from an inhibition of a guanine nucleotide regulatory protein activation, and the interaction between guanine nucleotide regulatory protein and phospholipase C. While the precise site of this inhibition is not presently known, the inhibition by cyclic GMP is dependent upon the addition of ATP and probably entails a phosphorylation event since adenylylimidodiphosphate can not substitute for the ATP requirement.
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PMID:Mechanism of cyclic GMP inhibition of inositol phosphate formation in rat aorta segments and cultured bovine aortic smooth muscle cells. 215 23

Physiologic responses mediated by calcium-mobilizing receptors are initiated by the phospholipase C-catalyzed generation from phosphatidyl inositol (4,5)-bisphosphate of two intracellular second messengers: inositol (1,4,5)-trisphosphate, which induces the release of calcium from intracellular stores, and diacylglycerol, which stimulates protein kinase C activity. Recent studies illustrating guanine nucleotide dependence for hormonal stimulation of membrane phospholipase C suggest involvement of a guanine nucleotide regulatory protein (G protein) in phosphoinositide/Ca2+ signaling. Kinetic analysis indicates that the receptor-stimulated phospholipase C catalytic cycle expresses properties similar to those described in detail for receptor and G protein-regulated adenylate cyclase. However, the identity of the phospholipase C-associated G protein remains to be established, and available data suggest that different G proteins (at least two) may be involved in a tissue- and/or receptor-specific manner. The identity of the phospholipase C involved in the action of calcium-mobilizing hormones also has not been established. Multiple forms of membrane-associated and cytosolic phospholipase C enzymes have been described during the last few years, which increases the apparent complexity of the system. The identification and purification of the G protein(s) and the phospholipase C enzyme(s) of this important signaling system followed by unambiguous reconstitution of their physiologic activities represent major challenges in this field for the coming years.
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PMID:G protein-dependent regulation of phospholipase C by cell surface receptors. 215 58

Recent studies have shown that, in addition to its well-known action to stimulate adenylate cyclase activity, parathyroid hormone (PTH) may stimulate the inositol phosphate second messenger system in its target tissues, bone and kidney. We have developed a membrane preparation of canine renal cortex to test this hypothesis. We also have examined the potential role of guanine nucleotides on the formation of inositol phosphates (IPs) in this tissue. Collagenase-dispersed tubules were labeled with [3H]inositol, and membranes containing labeled phospholipase C (PLC) substrates ([3H]phosphatidyl inositol, [3H]phosphatidylinositol monophosphate, and [3H]phosphatidylinositol bisphosphate) were prepared. bPTH-(1-34) (100 nM) rapidly increased levels of all measured [3H]IPs (IP1, IP2, and IP3) 1.6-1.7-fold within the first 30 s of stimulation. The half-maximal concentration for the response to bPTH-(1-34) was approximately 8 nM. GTP gamma S (100 microM), a nonhydrolyzable analog of GTP, also increased levels of the three [3H]IPs (1.8 to 2.8-fold). The half-maximal concentration for the response to GTP gamma S was approximately 30 microM. In the presence of GTP gamma S, bPTH-(1-34) increased levels of IPs by up to 2.7 times more than GTP gamma S alone. The results indicate that bPTH-(1-34) can stimulate the formation of inositol phosphates in the kidney and suggest that PTH may activate a receptor coupled to this effect through a guanine nucleotide regulatory protein.
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PMID:Parathyroid hormone stimulates formation of inositol phosphates in a membrane preparation of canine renal cortical tubular cells. 218 14

The allergic mediator release inhibitor 3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo[3,2-b]indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitor of human neutrophil functions in vitro. Over a concentration range from 1 to 100 mumol CI-922 inhibits the chemotactic response of neutrophils to the synthetic chemotaxin N-formyl-methionyl-leucyl-phenylalanine (FMLP). CI-922 also inhibits respiratory and secretory responses of neutrophils in response to agents that stimulate phospholipase C-dependent phosphoinositide hydrolysis to generate the second messengers inositol 1,4,5, trisphosphate and 1,2 diacylglycerol, including: the plasma membrane receptor-specific ligands FMLP and C5a; serum-opsonized zymosan; concanavalin A; and the guanine nucleotide regulatory protein-specific stimulus guanosine-5'-0-(3-thiotriphosphate) (GTP gamma S). CI-922 also inhibits neutrophil functions stimulated by the calcium ionophore A23187. In contrast, CI-922 does not inhibit neutrophil responses to protein kinase C-specific stimuli such as phorbol 12-myristate 13-acetate (PMA) or L-alpha-1,2 dioctanoylglycerol (DiC8). CI-922 also fails to inhibit the synergistic activation of the respiratory burst by suboptimal concentrations of PMA and calcium ionophore A23187. The observation that CI-922 inhibits neutrophil responses to a variety of soluble and particulate stimuli, excluding protein kinase C-specific stimuli, allows us to postulate the site of action of the compound. We propose that CI-922 inhibits neutrophil activation at a site distal to signal transduction through the guanine nucleotide regulatory protein required for second messenger generation but proximal to phosphorylation reactions mediated by protein kinase C and calmodulin-dependent protein kinases.
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PMID:Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: differential inhibition of responses to a variety of stimuli. 243 26

Stimulation of P2-purinergic receptors by ATP resulted in activation of phosphorylase, which was associated with marked production of inositol trisphosphate (Ins-P3), in rat hepatocytes. ATP also inhibited forskolin-induced accumulation of cAMP in the presence of a phosphodiesterase inhibitor. On the contrary, adenosine or AMP never inhibited the cAMP accumulation, but increased hepatocyte cAMP; the stimulation was antagonized by a methylxanthine. Thus, P1-purinergic receptors are linked to adenylate cyclase in a stimulatory fashion in hepatocytes. Various kinds of purine nucleotides stimulating P2-receptors can be divided into two groups on the basis of their relative abilities to stimulate Ins-P3 production and to inhibit cAMP accumulation; the first group including adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S), ADP, 5-adenylyl imidodiphosphate, GTP, and guanosine 5'-O-(3-thiotriphosphate) has an efficacy similar to that of ATP, and the second group of nucleotides including alpha, beta-methyleneadenosine 5'-triphosphate, beta, gamma-methyleneadenosine 5'-triphosphate (App(CH)2)p), and GDP exerts considerable inhibitory effects on cAMP accumulation, but only slight effects on inositol lipid metabolism. Treatment of hepatocytes with islet-activating protein, pertussis toxin, blocked the nucleotide-induced inhibition of cAMP accumulation, but exerted only a small effect on Ins-P3 production. In membranes prepared from hepatocytes, forskolin-stimulated adenylate cyclase was inhibited by GTP. This GTP-induced inhibition of the enzyme was susceptible to islet-activating protein and dependent on the concentration of ATP (or its derivatives, ATP gamma S or App(CH2)p). It is concluded that there are two types of P2-purinergic receptors: one is linked to adenylate cyclase via an inhibitory guanine nucleotide regulatory protein (Gi) and the other is linked to phospholipase C.
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PMID:P2-purinergic receptors are coupled to two signal transduction systems leading to inhibition of cAMP generation and to production of inositol trisphosphate in rat hepatocytes. 244 92


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