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)

Activation of human platelets by cross-linking of the platelet low-affinity IgG receptor, the Fc gamma receptor IIA (Fc gamma-RIIA), or by collagen is associated with rapid phosphorylation on tyrosine of the non-receptor tyrosine kinase syk. Phosphorylation is still observed, albeit sometimes reduced, in the presence of a combination of a protein kinase C inhibitor, Ro 31-8220, and the intracellular calcium chelator, BAPTA-AM, demonstrating independence from phosphoinositide-specific phospholipase C (PLC) activity. In contrast, the combination of Ro 31-8220 and BAPTA-AM completely inhibits phosphorylation of syk in thrombin-stimulated platelets. Phosphorylation of syk increases its autophosphorylation activity measured in a kinase assay performed on syk immunoprecipitates. Fc gamma-RIIA also undergoes phosphorylation in syk immunoprecipitates from platelets activated by cross-linking of Fc gamma-RIIA but not by collagen, suggesting that it associates with the kinase. Consistent with this, tyrosine-phosphorylated Fc gamma-RIIA is precipitated by a glutathione S-transferase (GST) fusion protein containing the tandem src homology (SH2) domains of syk from Fc gamma-RIIA- but not collagen-activated cells. Two uncharacterized tyrosine-phosphorylated proteins of 40 and 65 kDa are uniquely precipitated by a GST fusion protein containing the tandem syk-SH2 domains in collagen-stimulated platelets. A peptide based on the antigen recognition activation motif (ARAM) of Fc gamma-RIIA, and phosphorylated on the two tyrosine residues found within this region, selectively binds syk from lysates of resting platelets; this interaction is not seen with a non-phosphorylated peptide. Kinase assays on Fc gamma-RIIA immunoprecipitates reveal the constitutive association of an unidentified kinase activity in resting cells which phosphorylates a 67 kDa protein. Syk is not detected in Fc gamma-RIIA immunoprecipitates from resting cells but associates with the receptor following activation and, together with Fc gamma-RIIA, is phosphorylated in the kinase assay in vitro. These results demonstrate that syk is activated by Fc gamma-RIIA cross-linking and collagen, independent of PLC, suggesting that it may have an important role in the early events associated with platelet activation. The association of syk with Fc gamma-RIIA appears to be mediated through the tandem SH2 domains in syk and the ARAM motif of Fc gamma-RIIA. A similar interaction may underlie the response to collagen, suggesting that its signalling receptor contains an ARAM motif.
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PMID:Syk interacts with tyrosine-phosphorylated proteins in human platelets activated by collagen and cross-linking of the Fc gamma-IIA receptor. 748 83

ATP produced whole-cell potassium currents in cultured endothelial cells of the bovine brain cortical arteries. P2 purinoceptor agonists evoked similar currents with the order of their potency: 2-methylthio ATP > ATP >> alpha, beta-methylene ATP > or = UTP > or = ADP >> AMP. ATP-evoked currents were inhibited by GDP beta S, but not by pertussis toxin (PTX). Furthermore, a phospholipase C (PLC) inhibitor, protein kinase C inhibitor, or cAMP-dependent protein kinase inhibitor had no effect on the currents. In addition to these effects, ATP enhanced intracellular free Ca2+ concentration ([Ca2+]i) in the presence and absence of extracellular Ca2+, and this [Ca2+]i increase was not inhibited by a PLC inhibitor. These results, thus, provide an indication that ATP activates the potassium channel and enhances [Ca2+]i via a P2Y purinoceptor linked to a PTX-insensitive G-protein, which is not involved in a PLC-mediated signaling pathway.
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PMID:ATP activates the potassium channel and enhances cytosolic Ca2+ release via a P2Y purinoceptor linked to pertussis toxin-insensitive G-protein in brain artery endothelial cells. 748 26

To study the possible postreceptor mechanisms of prostaglandin E2 in modulating the male newt Triturus carnifex androgen synthesis, during reproduction, testes were in vitro superfused with medium alone, prostaglandin E2, protein kinase C activator (phorbol-12-myristate-13-acetate), prostaglandin E2 plus protein kinase C inhibitor (staurosporine), prostaglandin E2 plus phospholipase C inhibitor (compound 48/80), cAMP analog (dibutyryl cAMP), adenylate cyclase activator (forskolin), prostaglandin E2 plus AC inhibitor (2-0-methyladenosine), prostaglandin E2 plus protein kinase A inhibitor (H-89). In January (reproduction beginning), prostaglandin E2 and phorbol-12-myristate-13-acetate increased androgens, while staurosporine and compound 48/80 counteracted the prostaglandin E2 effect. In March (reproduction ending), prostaglandin E2, dibutyryl cAMP and forskolin decreased androgens, while 2-0-methyladenosine and H-89 counteracted the prostaglandin E2 effect. These data suggest that in Triturus carnifex prostaglandin E2 increases testicular androgens synthesis via phospholipase C at reproduction beginning; on the contrary, this prostaglandin decreases androgens via adenylate cyclase at reproduction ending.
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PMID:Androgen synthesis modulation by prostaglandin E2 is differentially mediated via adenylate cyclase and phospholipase C in the testis of the crested newt, Triturus carnifex: in vitro studies. 759 91

We showed previously that a single species of cloned PTH/PTH-related peptide (PTHrP) receptors, when stably expressed in LLC-PK1 kidney cells, couples to multiple second messenger signals and biological responses. To address the linkages of individual messenger signals to specific biological responses in these cells, we examined the relations among PTH/PTHrP receptor expression, PTH-activated phospholipase C (PLC) and adenylyl cyclase, and PTH-regulated phosphate transport in LLC-PK1 cells that stably express cloned rat PTH/PTHrP receptors. Among 18 such subclones, PTH stimulation of intracellular cAMP accumulation was nearly equivalent, despite differences in receptor density ranging from 20,000-400,000 sites/cell. In contrast, activation of PLC by PTH was directly and continuously dependent upon receptor density. PTH-stimulated phosphate uptake also was strongly dependent upon receptor expression, correlated well with PLC activity, was mimicked by active phorbol esters but not by cAMP analogs or forskolin, and was strikingly inhibited by the protein kinase C inhibitor, staurosporine. The peptide analog [Arg2]human PTH-(1-34), which significantly stimulated cAMP accumulation but failed to activate PLC, also did not increase phosphate uptake. We conclude that in LLC-PK1 cells, PTH-modulated PLC activation, unlike adenylyl cyclase activation, is strongly dependent upon PTH/PTHrP receptor density. This feature is reflected in the analogous relation between receptor density and PTH regulation of phosphate uptake, which appears to be mediated via a PKC-dependent pathway in these transfected cells. The results suggest that regulation of PTH/PTHrP receptor expression on target cells may provide a mechanism for altering the character as well as the magnitude of the signaling response to the hormone.
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PMID:Parathyroid hormone (PTH)/PTH-related peptide receptor density modulates activation of phospholipase C and phosphate transport by PTH in LLC-PK1 cells. 764 96

The anaphylatoxin C5a receptor activates the Ras/Raf/mitogen-activated protein (MAP) kinase pathway in human neutrophils. The signal pathways involved in Ras/Raf/MAP kinase activation in response to C5a and other chemoattractant receptors is poorly understood. Stimulation of the C5a receptor expressed in HEK293 cells results in modest MAP kinase activation, which is inhibited by pertussis toxin-catalyzed ADP-ribosylation of G(i). Coexpression of the C5a receptor and the G16 alpha subunit (alpha 16) results in the G16-mediated activation of phospholipase C beta and a robust MAP kinase activation. Pertussis toxin treatment of C5a receptor/alpha 16-cotransfected cells inhibits C5a stimulation of MAP kinase activity approximately 60% relative to the control response. Similarly, the protein kinase C inhibitor, GF109203X inhibits activation of MAP kinase activation in C5a receptor/alpha 16-cotransfected cells by 60%; the protein kinase C inhibitor does not affect the modest C5a receptor response in the absence of alpha 16 expression. These results demonstrate that two independent signals are required for the maximal activation of MAP kinase by G protein-coupled receptors.
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PMID:Mitogen-activated protein kinase activation requires two signal inputs from the human anaphylatoxin C5a receptor. 764 93

A431 cells, a human epidermoid carcinoma, possess specific [3H]platelet-activating factor (PAF) and [3H]WEB 2086 binding sites indicating the presence of PAF receptors. PAF-stimulated PLC as determined by the increase in inositol phosphate levels. Pretreatment of A431 cells with genistein, a putative tyrosine kinase inhibitor, abolished the ability of PAF to activate PLC, whereas pretreatment with staurosporine, a protein kinase C inhibitor, potentiated the ability of PAF to activate PLC. Pretreatment of A431 cells with phorbol-12-myristate-13-acetate, a protein kinase C activator, blocked PAF-stimulated PLC. Overnight exposure of cells to pertussis toxin (PT) partially blocked the ability of PAF to stimulate PLC. Based on these observations the involvement of PT-sensitive and -insensitive guanine nucleotide-binding protein(s) (G-protein) as well as the role of tyrosine kinase in the activation of PLC by PAF was considered further. PT treatment of A431 cell membranes obliterated PAF-stimulated GTPase and indicated that PT-insensitive membrane-associated G-proteins were not involved in PAF actions. In alpha-toxin permeabilized cells, PT blocked GTP-gamma-S potentiation of PLC activation by PAF, thus suggesting that PT-insensitive G-proteins were not involved in PAF activation of PLC in A431 cells. PAF stimulated tyrosine kinase activity as observed with the increase in radioactivity associated with proteins immunoprecipitated with polyclonal antibodies to phosphotyrosine residues. This increase was blocked by PAF receptor antagonists, CV 6209 and TCV 309, and by pretreatment with genistein. PAF also activated the phosphorylation of pp60c-src and Src associated proteins in A431 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of guanine nucleotide-binding protein and tyrosine kinase in platelet-activating factor activation of phospholipase C in A431 cells: proposal for dual mechanisms. 768

Linoleic acid (18:2n-6), linolenic acid and eicosatrienoic acid stimulated fluid reabsorption in locust rectum. Only 18:2n-6 was able to enhance phospholipase C activity, inositol(1,4,5) trisphosphate production and to increase cytosolic free Ca2+ concentrations in epithelial cells via the opening of L-type Ca2+ channels. These effects resemble those exerted by neuroparsin, an antidiuretic neuronal hormone extracted from the storage lobes of the locust corpora cardiaca. As for neuroparsin, the effects of 18:2n-6 were abolished after pre-treatment with the protein kinase C inhibitor, polymyxin B. The results were consistent with a regulation of neuroparsin-sensitive phospholipase C activity by 18:2n-6 under control of protein kinase C, possibly by increasing membrane fluidity. Cyclooxygenase inhibitors attenuated the effects of 18:2n-6. This demonstrated that the results should be produced via the metabolites of 18:2n-6 HODEs rather than the PUFA itself.
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PMID:Action of linoleic acid on phospholipase C activity at the rectal level of the African locust under the control of protein kinase C. 774 3

Effects of endothelin-3 on ganglionic transmission were investigated in dog cardiac sympathetic ganglia. Positive chronotropic responses to preganglionic stellate stimulation were inhibited by endothelin-3 (0.5-2 micrograms) given directly to the ganglia through the artery. To find possible inhibitory effects of the peptide at presynaptic sites, acetylcholine released from the isolated stellate ganglia was determined. The amount of acetylcholine released during preganglionic stimulation was reduced by exposure to endothelin-3 (10(-9) to 10(-6) M). A similar reduction of acetylcholine release was observed after application of a stable thromboxane A2, a thromboxane A2/prostaglandin H2 receptor agonist, U-46619, and prostaglandin E2 at concentrations from 10(-8) to 10(-4) M, but not by the same concentrations of prostaglandins F2 alpha and I2. The reduction elicited by endothelin-3 was unaffected by a phospholipase C inhibitor, neomycin, or a protein kinase C inhibitor, H-7, but was antagonized by pretreatment with phospholipase A2 inhibitors, dexamethasone or methylprednisolone, and by cyclooxygenase inhibitors, aspirin and indomethacin. In addition, the reduction also was antagonized by pretreatment with a thromboxane A2 synthetase inhibitor, OKY-046, and a specific thromboxane A2 receptor antagonist, S-145, but not by a specific prostaglandin E2 receptor antagonist, SC-19220. Furthermore, endothelin-3 (10(-7) M) stimulated the OKY-046- and indomethacin-sensitive formation of thromboxane A2 in the ganglia. These results indicate that endothelin-3 inhibits the sympathetic ganglionic transmission by reducing acetylcholine release at preganglionic terminals and that this inhibition seems to involve activation of endogenous thromboxane A2 production.
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PMID:Activation of endogenous thromboxane A2 biosynthesis mediates presynaptic inhibition by endothelin-3 of dog stellate ganglionic transmission. 781 66

Angiotensin II (Ang II) is an important regulator of aldosterone production by bovine adrenal glomerulosa (BAG) cells. Ang II interacts with a specific receptor coupled to a guanyl nucleotide-binding protein (G protein) that controls the activity of phospholipase C. A primary culture of BAG cells was used to study short-term desensitization of the Ang II receptor. After short exposures to Ang II, BAG cells lost some [125I]Ang II binding capacity. This loss was dependent on the duration of the pretreatment and on the concentration of Ang II used. A maximal loss of [125I]Ang II binding of 55 +/- 10% was observed after a pretreatment of 30 min with 30 nM Ang II. The EC50 was 1.3 +/- 0.6 nM (mean +/- SD of three experiments). The desensitization was readily reversible, since most of the binding capacity (higher than 90%) was recovered after a 60-min incubation, at 37 C, in the absence of Ang II. Scatchard studies revealed that the Ang II receptor of BAG cells exists under two affinity states with one dissociation constant of 0.2 nM and another dissociation constant of 1.5 nM. After a 30-min exposure of BAG cells to 10 nM Ang II, an important decrease of high affinity binding sites was observed. The maximal amount of binding sites was similar on control and desensitized cells (around 52,000 receptors per cell). GTP gamma S, a potent activator of G proteins, decreased [125I]Ang II binding to permeabilized BAG cells. This GTP gamma S effect was not observed on permeabilized BAG cells that had previously been desensitized with 10 nM Ang II. These results suggested that, similarly to GTP gamma S, short exposure to 10 nM Ang II caused the uncoupling of Ang II receptor from its G protein. DuP-753 (a selective AT1 angiotensin II type 1 receptor antagonist) markedly unhibited, whereas PD-123319 (a selective AT2 angioten II type 2 receptor antagonist) had no effect on Ang II receptor desensitization, indicating that the AT1 receptor subtype was responsible for the observed phenomenon. Pretreatment of BAG cells with staurosporine (a protein kinase C inhibitor) and R24571 (a calmodulin inhibitor) did not modify Ang II-induced desensitization of AT1 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Short-term desensitization of the angiotensin II receptor of bovine adrenal glomerulosa cells corresponds to a shift from a high to a low affinity state. 795 36

Complementary DNAs encoding delta, mu and kappa-opioid receptors have now been cloned and characterized. These receptors, which are members of the superfamily of seven transmembrane spanning receptors, share a high degree of amino acid sequence similarity among these receptors. From the similarity of the sequence, it is speculated that both the 1st and 2nd extracellular loop and the 4th membrane spanning domain are supposed to be involved in the opioid binding and subtype specificity. Because of the high similarity of the cytoplasmic regions' amino acid sequence, however, it seems that the signal transductions of delta, mu and kappa are very similar. In Xenopus oocytes expressing delta-opioid receptors and various kinds of GTP-binding protein alpha-subunits, the delta-agonist DSLET caused currents through Gi1 alpha (or Gi2 alpha)-phospholipase C mechanisms Neither G(o) alpha, Gq alpha, G11 alpha nor G14 alpha was involved in such delta-receptor-mediated responses. The higher concentration of DSLET (3-10 microM) showed a rapid desensitization upon repeated challenges. Such a rapid desensitization was purely homologous, and this was rescued by the pretreatment with protein kinase C inhibitor. Similar findings were also observed with mu and kappa-opioid receptors. These results suggest that the phosphorylation by protein kinase C is involved in the acute tolerance.
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PMID:[Signal transduction of cloned opioid receptors]. 795 15


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