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)

Ligand stimulation of the platelet-derived growth factor receptor (PDGF-R) results in rapid activation of the receptor tyrosine kinase, stimulation of phosphoinositide hydrolysis, an increase in intracellular free Ca2+ concentration ([Ca2+]i), and, ultimately, cellular proliferation. In a previous study, we demonstrated that staurosporine, a known inhibitor of protein kinase C, blocked PDGF-induced [Ca2+]i increases in Swiss mouse 3T3 fibroblasts by a mechanism that appeared unrelated to inhibition of protein kinase activity (Olsen, R., Melder, D., Seewald, M., Abraham, R., and Powis, G. (1990) Biochem. Pharmacol. 39, 968-972). In the present study, we report that staurosporine inhibits ligand-dependent PDGF-R tyrosine kinase activation in cell-free receptor preparations and in intact Swiss 3T3 cells. At the same concentrations (10(-8)-10(-6) M), staurosporine suppressed both the tyrosine phosphorylation of phospholipase C activity and the hydrolysis of phosphoinositides induced by PDGF stimulation of intact cells. In contrast, guanine nucleotide-binding protein-dependent phospholipase C activation induced by bradykinin or fluoroaluminate anion was relatively insensitive to staurosporine. A preferential inhibitory effect of staurosporine on signal generation by the PDGF-R was indicated by findings that epidermal growth factor receptor (EGF-R) tyrosine kinase activity and EGF-dependent phospholipase C in A-431 carcinoma cells were approximately 100-fold less sensitive to this drug. These data indicate that submicromolar concentrations of staurosporine inhibit PDGF-dependent phosphoinositide hydrolysis and Ca2+ mobilization through a proximal inhibitory effect on ligand-induced activation of the PDGF-R tyrosine kinase.
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PMID:Preferential inhibition of the platelet-derived growth factor receptor tyrosine kinase by staurosporine. 217 5

This study examines the mechanism of guanine nucleotide-binding protein (G protein) coupling of receptors to phospholipase C. The Xenopus oocyte has a muscarinic receptor-activated Cl- current that is mediated by inositol 1,4,5-trisphosphate. Modulation of the muscarinic receptor-evoked Cl- current was examined under voltage clamp in oocytes injected with resolved G-protein subunits. The presence of an alpha subunit of G proteins in oocytes was shown by pertussis toxin-labeling of a 41-kDa band in oocyte membranes. The presence of the beta subunit of G proteins was demonstrated by immunoblotting experiments with an antiserum (U-49) that is specific for the beta subunit. Pertussis toxin treatment of oocytes resulted in the uncoupling of muscarinic receptors from activation of the Cl- current. Cells microinjected with 1.5 ng of human erythrocyte beta gamma-subunit complex or 1.0 ng of bovine brain beta gamma-subunit complex showed approximately a 95% reduction in the evoked Cl- current. Cells injected with equal volumes of protein storage vehicle showed no change in response. Cells injected with boiled beta gamma subunits, bovine serum albumin, or resolved alpha subunits also showed no reduction in response. Cells injected with various concentrations of beta gamma subunits showed a concentration dependence with half-maximal inhibition of the muscarinic activated Cl- current at about 10 nM. Cells injected with 1.0 ng of bovine brain beta gamma subunits could not respond to bath-applied agonist but could generate the Cl- current on intracellular injection of inositol 1,4,5-trisphosphate. These observations suggest that there is a G protein responsible for muscarinic receptor-mediated signal transduction through phospholipase C and that it is an alpha beta gamma heterotrimer. It appears that the mode of action of the G protein in the phospholipase C system may be similar to that of the hormone-activated adenylyl cyclase.
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PMID:Beta gamma subunits of GTP-binding proteins inhibit muscarinic receptor stimulation of phospholipase C. 246 57

In neutrophils and several other phagocytes, a pertussis and cholera toxin-sensitive guanine nucleotide-binding protein (G-protein) couples the receptors for formyl methionine-containing chemotactic peptides to stimulation of phospholipase C. We used membranes of myeloid-differentiated HL 60 cells to study the role of Na+ in regulating both the interaction of the formyl peptide receptor with the chemotactic agonist, N-formyl-methionyl-leucyl-phenylalanine (FMLP), and the receptor-mediated activation of the G-protein. Monovalent cations (Na+ greater than Li+ greater than K+ greater than choline+) markedly inhibited the binding of the radiolabeled oligopeptide [3H]FMLP by specifically reducing the number of receptors in the high-affinity state. Half-maximal and maximal inhibition of peptide binding were seen at cation concentrations of approximately 20 and 200 mM, respectively. Inhibition of peptide binding by Na+ was observed in the presence and absence of divalent cations and was strictly additive to inhibition by the poorly hydrolyzable GTP analogue, guanosine-5'-O-(3-thiotriphosphate), or to ADP ribosylation of G-proteins by pertussis toxin. The inhibitory effect of Na+ on peptide binding coincided with a marked reduction of the potency of FMLP to stimulate a high-affinity GTPase. In contrast, the degree of FMLP-stimulated GTPase activity was markedly enhanced in the presence of Na+. This was largely due to the fact that Na+ reduced the agonist-independent basal GTPase activity in the same way but less so than pertussis toxin treatment. The results show that monovalent cations, Na+ in particular, regulate the interaction of the formyl peptide receptor with both the chemotactic agonist and the G-protein by acting on a single site, possibly located on the receptor itself. The observation that basal GTPase activity is markedly reduced by both Na+ and pertussis toxin treatment also suggests (a) that G-proteins interact with and are activated by receptors even in the absence of agonists and (b) that Na+ uncouples unoccupied receptors from G-protein interaction and activation.
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PMID:Na+ regulation of formyl peptide receptor-mediated signal transduction in HL 60 cells. Evidence that the cation prevents activation of the G-protein by unoccupied receptors. 251 70

In RBL-2H3 rat basophilic leukemia cells, Ag that crosslink IgE-receptor complexes stimulate the turnover of inositol phospholipids, the mobilization of Ca2+ from intra- and extracellular sources, the release of serotonin and other substances from granules and the transformation of the cell surface from a microvillous to a lamellar architecture. This study explores the role of GTP-binding proteins (G proteins) in the control of these biochemical and functional responses. We report that incubating RBL-2H3 cells for 4 h with 10 microM mycophenolic acid (MPA), an inhibitor of de novo GTP synthesis, reduces GTP levels by over 60% and causes an average reduction of 50% in Ag-stimulated serotonin release. This inhibition of secretion is associated with a 50% decrease in the rate of 45Ca2+ influx in MPA-treated cells. In contrast, Ag-stimulated inositol trisphosphate production is only slightly reduced, indicating that the phosphatidylinositol-specific phospholipase C can be activated by Ag in GTP-depleted cells. The membrane responses to IgE receptor cross-linking are unaffected by incubating cells with MPA. Exogenous guanine or guanosine protects the GTP pools in MPA-treated cells and permits normal ion transport and secretory responses to Ag; adenine does not. These results implicate a guanine nucleotide-binding protein in the control of IgE receptor-dependent signal transduction in RBL-2H3 cells. This protein may particularly control the Ca2+ influx pathway that is essential for secretion.
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PMID:Depletion of guanine nucleotides with mycophenolic acid suppresses IgE receptor-mediated degranulation in rat basophilic leukemia cells. 252 48

Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H]inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylation, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.
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PMID:Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain. 253 62

The ability of alcohols to regulate inositol lipid-specific phospholipase C (phosphoinositidase C) was examined in turkey erythrocyte ghosts prepared by cell lysis of erythrocytes which were prelabeled with [3H] inositol. Guanosine 5'-[gamma-thiotriphosphate] GTP[S] stimulated the production of both [3H]inositol bisphosphate (18-fold) and [3H]inositol trisphosphate (6-fold) in this system. The accumulation of [3H]inositol bisphosphate and [3H]inositol trisphosphate was linear up to 8 min following an initial lag period of 1-2 min. Ethanol (300 mM) reduced the lag period for [3H]inositol phosphate accumulation at submaximal GTP[S] concentrations and caused a shift to the left (3-fold) in the dose-response curve. Other short chain alcohols, methanol (300 mM), 1-propanol (200 mM), and 1-butanol (50 mM) also enhanced the accumulation of [3H] inositol phosphates in the presence of submaximal GTP[S] concentrations. Receptor activation by the purinergic agonist adenosine 5'-[beta-thio]disphosphate (ADP[S]) (10 microM) also reduced the lag period for [3H] inositol phosphate formation and shifted the GTP[S] dose response to the left (10-fold). In addition, ADP[S] increased the response to maximal GTP[S] concentrations. The formation of [3H]inositol phosphates induced by GTP[S] was associated with a concomitant decrease in labeling of both [3H]phosphatidylinositol monophosphate and [3H]phosphatidylinositol bisphosphate, but no decrease in [3H]phosphatidylinositol was observed. All of the alcohols tested enhanced the breakdown of [3H]polyphosphoinositides in the presence of GTP[S]. The dose response to guanosine 5'-[beta gamma-imino]triphosphate for [3H]inositol phosphate formation was displaced to the left by ethanol (300 mM) and ADP[S] (10 microM) (2- and 7-fold), respectively. ADP[S] also enhanced the maximal response to guanosine 5'-[beta gamma-imino]triphosphate. The [3H]inositol phosphate formation produced in response to NaF was unaffected by either ethanol or receptor activation. These results indicate that alcohols initiate an activation of phosphoinositidase C, mediated at the level of the regulatory guanine nucleotide-binding protein.
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PMID:Short chain alcohols activate guanine nucleotide-dependent phosphoinositidase C in turkey erythrocyte membranes. 254 Jan 62

The Drosophila and Lucilia photoreceptor mutants, trp and nss, respond like wild-type flies to a short pulse of intense light or prolonged dim light; however, upon continuous intense illumination, the trp and nss mutants are unable to maintain persistent excitation. This defect manifests itself by a decline of the receptor potential toward baseline during prolonged intense illumination with little change in the shape or amplitude of the quantal responses to single photons (quantum bumps). Previous work on the trp and nss mutants suggests that a negative feedback loop may control the rate of bump production. Chemical agents affecting different steps of the phototransduction cascade were used in conjunction with light to identify a possible branching point of the feedback loop and molecular stages which are affected by the mutation. Fluoride ions, which in the dark both excite and adapt the photoreceptors of wild-type flies, neither excite nor adapt the photoreceptors of the trp and nss mutants. The hydrolysis-resistant analogue, GTP gamma S, which excites the photoreceptors of wild-type flies, resulting in noisy depolarization, markedly reduces the light response of both mutant flies. Intracellular recordings revealed, however, that the inhibitory effect of GTP gamma S on the nss mutant was accompanied neither by any significant depolarization nor by an increase in the noise, and thus was very different from the effect of a dim background light. The combination of inositol trisphosphate and diphosphoglycerate (InsP3 + DPG), which efficiently excites the photoreceptors of wild-type Lucilia, also excites the photoreceptors of nss Lucilia mutant. The InsP3 + DPG together act synergistically with light to accelerate the decline of the response to light in the mutant flies. These results suggest that the fly phototransduction pathway involves a feedback regulatory loop, which branches subsequent to InsP3 production and regulates guanine nucleotide-binding protein (G protein)-phospholipase C activity. A defect in this regulatory loop, which may cause an unusually low level of intracellular Ca2+, severely reduces the triggering of bumps in the mutants during intense prolonged illumination.
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PMID:Chemical excitation and inactivation in photoreceptors of the fly mutants trp and nss. 260 31

The heterologous desensitization of the bradykinin (BK)-induced increase in intracellular Ca2+ concentration ([Ca2+]i) by neurotensin was studied in neuroblastoma x glioma hybrid NG108-15 cells. The addition of neurotensin to the cells resulted in an increase in [Ca2+]i and an increase in the formation of inositol phosphates in Ca2+-free medium. Pretreatment of the cells with neurotensin resulted in 43% decrease in the BK-induced increase of [Ca2+]i. The increase in [Ca2+]i induced by ionomycin, which causes Ca2+ release from the intracellular pool, was not decreased by pretreatment with neurotensin. This indicates that the inhibitory effect of neurotensin on the BK-induced increase of [Ca2+]i was not due to depletion of the intracellular Ca2+ pool. Pretreatment with neurotensin also caused a 47% decrease in the BK-induced formation of inositol trisphosphates (IP3). This decrease was not due to depletion of phosphatidylinositol bisphosphates. Neurotensin did not inhibit [3H]BK binding to cell membranes. These results show that neurotensin desensitizes the BK responses of NG108-15 cells, heterologously, perhaps by changes in phospholipase C and/or guanine nucleotide-binding protein (G-protein).
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PMID:Heterologous desensitization of bradykinin-induced phosphatidylinositol response and Ca2+ mobilization by neurotensin in NG108-15 cells. 272 52

Cortical slices from rat brain were used to study carbachol-stimulated inositol phospholipid hydrolysis. Omission of calcium during incubation of slices with [3H]inositol increased its incorporation into receptor-coupled phospholipids. Carbachol-stimulated hydrolysis of [3H]inositol phospholipids in slices was dose-dependent, was affected by the concentrations of calcium and lithium present and resulted in the accumulation of mostly [3H]inositol-1-phosphate. Incubation of slices with N-ethylmaleimide or a phorbol ester reduced the response to carbachol. Membranes prepared from cortical slices labeled with [3H]inositol retained the receptor-stimulated inositol phospholipid hydrolysis reaction. The basal rate of inositol phospholipid hydrolysis was higher than in slices and addition of carbachol further stimulated the process. Addition of GTP stimulated inositol phospholipid hydrolysis, suggesting the presence of a guanine nucleotide-binding protein coupled to phospholipase C. Carbachol and GTP-stimulated inositol phospholipid hydrolysis in membranes was detectable following a 3 min assay period. In contrast to slices, increased levels of inositol bisphosphate and inositol trisphosphate were detected following incubation of membranes with carbachol. These results demonstrate that agonist-responsive receptors are present in cortical membranes, that the receptors may be coupled to phosphatidylinositol 4, 5-bisphosphate, rather than phosphatidylinositol, hydrolysis and that a guanine nucleotide-binding protein may mediate the coupling of receptor activation to inositol phospholipid hydrolysis in brain.
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PMID:Modulation of carbachol-stimulated inositol phospholipid hydrolysis in rat cerebral cortex. 281 54

Stimulation of muscarinic receptors in dissociated embryonic chick heart cells promotes the hydrolysis of the phosphoinositides resulting in accumulation of the breakdown products inositol trisphosphate, bisphosphate, and monophosphate (InsP3, Insp2, and InsP, respectively). [3H]InsP3 and [3H]InsP2 are significantly elevated within 10 seconds of carbachol addition, while there is a lag in the accumulation of [3H]InsP. The time courses of the formation of the inositol phosphates suggest that carbachol activates a polyphosphoinositide-specific phospholipase C resulting in the formation of InsP3, which is subsequently metabolized to InsP2 and InsP. High-performance liquid chromotography analysis demonstrates the formation of both naturally occurring InsP3 isomers (Ins-1,4,5-P3 and Ins-1,3,4,-P3) and of inositol tetrakisphosphate (InsP4) as well. To investigate whether a guanine nucleotide-binding protein couples receptor stimulation to phosphoinositide (PI) hydrolysis in the heart, we developed a saponin-permeabilized cell preparation that would allow external manipulation of the intracellular guanosine triphosphate (GTP) concentration. In the permeabilized cell preparation, guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) stimulates the accumulation of [3H]InsP, [3H]InsP2, [3H]InsP3, and [3H]InsP4. The effect of GTP gamma S is half-maximal at 1 microM and maximal above 100 microM. In contrast, GTP gamma S is ineffective in promoting PI hydrolysis in the nonpermeabilized cell except at high concentrations. Other guanine nucleotides also lead to the accumulation of [3H]InsP in the permeabilized cell, while 5'-adenylylimidodiphosphate does not. Carbachol also stimulates PI hydrolysis in the permeabilized cell preparation although it is less effective than in the intact cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Guanine nucleotide-dependent inositol trisphosphate formation in chick heart cells. 282 11


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