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 present experiments were performed to determine pathways responsible for arachidonic acid release stimulated by cholecystokinin (CCK) and phorbol ester, 4 beta-phorbol 12-myristate 13-acetate (PMA), and the roles of pathways in the secretory response in dispersed acini from guinea pig pancreas. Both CCK-octapeptide (CCK-OP) and PMA increased intracellular arachidonic acid. To determine the source of released arachidonic acid, we measured the effects of PMA and CCK-OP on cellular 1,2-diacylglycerol and lysophosphatidylcholine (LPC) and of diglyceride lipase inhibitor RHC 80267 on [3H]arachidonic acid release. Both PMA and CCK-OP increased 1,2-diacylglycerol and LPC. RHC 80267 had no effect on LPC but inhibited the increase in [3H]arachidonic acid release with a concentration of CCK-OP that was maximal for enzyme secretion. The increase in [3H]arachidonic acid release with PMA or a supramaximal concentration of CCK-OP was not inhibited by RHC 80267. In parallel fashion, RHC 80267 inhibited amylase release caused by maximally effective concentrations of CCK-OP but not that caused by PMA or by supramaximally effective concentrations of CCK-OP. Arachidonic acid stimulated amylase release. Exogenous addition of phospholipase A2 caused increases in [3H]arachidonic acid release, LPC formation, and amylase release. The results indicate that there are at least two pathways responsible for the increase in free cellular arachidonic acid stimulated by pancreatic agonists. One is sequential action of phospholipase C and diglyceride lipase on phosphatidylinositol. The other is a phospholipase A action on phosphatidylcholine. The results also suggest a stimulatory role for both pathways in the secretory response.
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PMID:Dual pathways for agonist-stimulated arachidonic acid release in pancreatic acini: roles in secretion. 170 48

Protein tyrosine phosphorylation has not been considered to be important for cellular activation by phospholipase C-linked vasoactive peptides. We found that endothelin, angiotensin II, and vasopressin (AVP), peptides that signal via phospholipase C activation, rapidly enhanced tyrosine phosphorylation of proteins of approximate molecular mass 225, 190, 135, 120, and 70 kDa in rat renal mesangial cells. The phosphorylated proteins were cytosolic or membrane-associated, and none were integral to the membrane, suggesting that the peptide receptors are not phosphorylated on tyrosine. Epidermal growth factor (EGF), which does not activate phospholipase C in these cells, induced the tyrosine phosphorylation of its own 175-kDa receptor, in addition to five proteins of identical molecular mass to those phosphorylated in response to endothelin, AVP, and angiotensin II. This suggests that in mesangial cells there is a common signaling pathway for phospholipase C-coupled agonists and agonists classically assumed to signal via receptor tyrosine kinase pathways, such as EGF. The phorbol ester, phorbol 12-myristate 13-acetate, and the synthetic diacylglycerol, oleoyl acetylglycerol, stimulated the tyrosine phosphorylation of proteins identical to those phosphorylated by the phospholipase C-linked peptides, suggesting that protein kinase C (PKC) activation is sufficient to active tyrosine phosphorylation. However, the PKC inhibitor, staurosporine, and down-regulation of PKC activity by prolonged exposure to phorbol esters completely inhibited tyrosine phosphorylation in response to PMA but not to endothelin, AVP, or EGF. In conclusion, endothelin, angiotensin II, and AVP enhances protein tyrosine phosphorylation via at least two pathways, PKC-dependent and PKC-independent. Although activation of PKC may be sufficient to enhance protein tyrosine phosphorylation, PKC is not necessary and may not be the primary route by which these agents act. At least one of these pathways is shared with the growth factor EGF, suggesting not only common intermediates in the signaling pathways for growth factors and vasoactive peptides but also perhaps common cellular tyrosine kinases which phosphorylate these intermediates.
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PMID:Endothelin, vasopressin, and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. 170 22

Monoclonal antibodies (mAb) to differentiation antigens frequently influence the in vitro function of antigen-bearing cells. We characterized a 32-36-kDa membrane protein expressed on guinea pig lymphocytes and Langerhans cells. A series of independently derived mAb to this protein, now called guinea pig T cell activation antigen (gpTAA), induced strong proliferation of T cells in vitro. Cross-linking of the mAb by a secondary antibody (rabbit anti-mouse Ig) and costimulation with phorbol 12-myristate 13-acetate were required for activation. Treatment of the cells with phosphatidylinositol-specific phospholipase C greatly reduced the amount of antigen expressed on the cell surface as measured by flow cytometry analysis. This finding indicates that the antigen is anchored to the cell membrane via phosphatidylinositol linkage as shown similarly for other membrane proteins with T cell activating properties, e.g. Thy-1 and Ly-6. The guinea pig protein differs, however, in its molecular weight and tissue distribution from similar proteins identified in the mouse or in the rat system. Unlike Thy-1, gpTAA is also expressed on B Lymphocytes and Langerhans cells. Considering the previously described involvement in cellular adhesion, and the functional characteristics reported here, gpTAA might represent a new species of differentiation antigen with T cell-activating capacity.
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PMID:T cell proliferation induced by monoclonal antibodies to a phosphatidylinositol-linked differentiation antigen of guinea pig lymphocytes. 170 3

Previous studies have demonstrated that bradykinin hyperpolarizes the cell membrane of subconfluent MDCK cells by increase of the potassium conductance. The present study has been performed to elucidate the intracellular mechanisms involved. To this end, the effects of bradykinin on the potential difference across the cell membrane (PD), on formation of inositol phosphates, and on intracellular calcium concentration (Cai) have been analyzed in cells without or with pretreatment with pertussis toxin or 12-O-tetradecanoylphorbol 13-acetate diester (TPA). In untreated cells, bradykinin leads to a transient increase of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate, increase of Cai, activation of potassium channels and hyperpolarization of the cell membrane. The effects of bradykinin on PD and Cai are still present in the absence of extracellular calcium. In cells pretreated with pertussis toxin the effect of bradykinin on inositol trisphosphate formation is almost abolished but bradykinin still leads to a transient increase of Cai and PD in the presence and absence of extracellular calcium. In cells pretreated with TPA the bradykinin-induced increase of inositol trisphosphate formation is blunted, the bradykinin-induced increase of Cai abolished, but the bradykinin-induced hyperpolarization still present. The observations indicate that bradykinin increases Cai in part by phorbol ester and pertussis toxin sensitive activation of phospholipase C. In addition, bradykinin is capable of enhancing Cai by utilizing pertussis toxin insensitive mechanisms. Furthermore, bradykinin is able to transiently enhance the potassium conductance without a general increase of intracellular calcium.
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PMID:Cellular mechanisms of bradykinin-induced hyperpolarization in renal epitheloid MDCK-cells. 170 74

Dual inhibitory and stimulatory actions of guanine nucleotides on luteinizing-hormone (LH) exocytosis were observed in primary sheep gonadotropes permeabilized with staphylococcal alpha-toxin. At resting cytosolic [Ca2+]free (pCa 7), 5'-[gamma-thio]triphosphate (GTP[S]) and guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) stimulated rapid LH exocytosis, which was maximal between 5 and 10 min. GTP[S] and p[NH]ppG had similar potencies (50% of maximum effect at 20-50 microM), but the effect of p[NH]ppG was more prolonged. Experiments carried out in the presence of saturating concentrations of phorbol 12-myristate 13-acetate (PMA), or in PMA-desensitized cells, suggested that stimulation by p[NH]ppG is mediated by a mechanism additional to protein kinase C (PKC) activation. Furthermore, p[NH]ppG stimulated LH exocytosis in the presence of saturating cyclic AMP (cAMP) concentrations, although its effect was less than additive. However, when both PMA and cAMP were present, p[NH]ppG did not stimulate a further increase in the rate of LH exocytosis. In contrast, pretreatment of cells with GTP[S] at low [Ca2+]free markedly inhibited subsequent responses to Ca2+, cAMP, PMA, and cAMP plus PMA. This inhibitory effect required lower GTP[S] concentrations than the stimulatory effect (50% inhibition at 1-10 microM), and was not observed with p[NH]ppG. A similar inhibition was observed with adenosine 5'-[gamma-thio]triphosphate, probably by its conversion into GTP[S]. These results suggest that the stimulatory actions of guanine nucleotides can be accounted for by the combined activation of PKC and generation of cAMP, resulting from activation of conventional signal-transducing GTP-binding proteins. The inhibitory effect of GTP[S] can be clearly distinguished and indicates the involvement of a distinct GTP-binding protein in exocytosis at a site distal to second-messenger generation.
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PMID:Inhibition of luteinizing-hormone exocytosis by guanosine 5'-[gamma-thio]triphosphate reveals involvement of a GTP-binding protein distal to second-messenger generation. 170 5

The CDw50 differentiation antigen is defined by 101-1D2 and 140-11 monoclonal antibodies (mAb), both produced and characterized in our laboratory. This molecule is broadly expressed on hematopoetic cells but not on other cells. In this report we show that these 2 mAb recognize different epitopes of the same molecule, which are resistant to neuraminidase and proteases. We also demonstrate that the CDw50 antigen is expressed on thymocytes and T lymphocytes as an N-glycosylated glycoprotein monomer with a relative molecular weight (Mr) of 130,000 daltons with intrachain disulfide bonds, and that this molecule is resistant to treatment with phosphatidylinositol (PI) phospholipase C and therefore probably not PI-anchored to the membrane. CDw50 is a poorly or non-constitutively phosphorylated molecule that becomes phosphorylated by treatment with phorbol 12-myristate 13-acetate (PMA) of peripheral blood mononuclear cells (PBMC). The addition of affinity-purified CDw50 mAb inhibits primary mixed lymphocyte culture (MLC) but not secondary MLC, cytotoxicity or proliferation induced by mitogens. The inhibition of alloreactivity is mediated at the level of both responding and stimulator cells.
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PMID:Involvement of the CDw50 molecule in allorecognition. 171 77

The role of lipid-bound second messengers in the regulation of neurotransmitter secretion is an important but poorly understood subject. Both bovine adrenal chromaffin cells and rat phoeochromocytoma (PC12) cells, two widely studied models of neuronal function, respond to bradykinin by generating phosphatidic acid (PA). This putative second messenger may be produced by two receptor-linked pathways: sequential action of phospholipase C (PLC) and diacylglycerol kinase (DAG kinase), or directly by phospholipase D (PLD). Here we show that bradykinin stimulation of chromaffin cells prelabelled (24 h) with 32Pi leads to production of [32P]PA which is not affected by 50 mM butanol. However, bradykinin stimulation of PC12 cells leads to [32P]PA formation, all of which is converted to phosphatidylbutanol in the presence of butanol. When chromaffin cells prelabelled with [3H]choline were stimulated with bradykinin there was no enhancement of formation of water soluble products of phosphatidylcholine hydrolysis. When chromaffin cells were permeabilised with pneumolysin and incubated in the presence of [gamma-32P]ATP, the formation of [32P]PA was still stimulated by bradykinin. These results show that, although both neuronal models synthesize PA in response to bradykinin, they do so by quite different routes: PLC/DAG kinase for chromaffin cells and PLD for PC12 cells. The observation that neither bradykinin nor tetradecanoyl phorbol acetate stimulate PLD in chromaffin cells suggests that these cells lack PLD activity. The conservation of PA formation, albeit by different routes, may indicate an essential role of PA in the regulation of cellular events by bradykinin.
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PMID:Lack of phospholipase D activity in chromaffin cells: bradykinin-stimulated phosphatidic acid formation involves phospholipase C in chromaffin cells but phospholipase D in PC12 cells. 171 14

In GH(1)2C1 rat pituitary cells treated with 5-azacytidine, the stimulatory effects exerted by vasoactive intestinal peptide (VIP), the GTP analogue guanyl-5'-yl imidodiphosphate (Gpp(NH)p), 12-O-tetradecanoyl phorbol 13-acetate, cholera toxin and pertussis toxin on the membrane-bound adenylyl cyclase were almost completely abolished. The corresponding inhibitory effect of somatostatin was increased. Alterations in adenylyl cyclase responsiveness began at the end of the drug treatment, and were most pronounced on day 5 after removal of 5-azacytidine. The cells subsequently and completely recovered after 10 days in the absence of the drug. Measurements of cholera toxin- and VIP-enhanced cyclic AMP levels in intact cells confirmed these results, and VIP appeared to have no stimulatory effect on GH secretion after 5-azacytidine treatment. Down-regulation of G alpha s RNA also occurred on day 5 after cessation of drug treatment. ADP-ribosylation subsequent to stimulation with pertussis toxin was markedly increased, indicating an enhancement of G alpha i and/or G alpha o. Furthermore, both basal and Gpp(NH)p-stimulated phospholipase C activities were augmented by pre-exposure to 5-azacytidine. Treatment of GH(1)2C1 rat pituitary tumour cells with 5-azacytidine therefore causes a marked but temporary increase in the ratio of G alpha i/G alpha s protein levels.
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PMID:Signal transduction alterations in GH(1)2C1 rat pituitary tumour cells following treatment with 5-azacytidine. 171 9

Stimulation of quiescent T lymphocytes to proliferate involves a complex series of events both between and within cells. At least 70 genes are known to be induced or activated from the time of the initial stimulation until DNA synthesis. While some of these gene products, e.g., interleukin-2 (IL-2) and IL-2 receptors, are required for proliferation, others, e.g., gamma-interferon and colony-stimulating factor, are ancillary to activated T cell function. Several biochemical signal transductions are among the early events. One of the earliest is phospholipase C-mediated hydrolysis of phosphatidylinositol leading to release of diacylglycerols and inositol phosphates, which in turn activate protein kinase C and elevate intracellular free calcium levels. The discovery that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) both enhances proliferation and activates protein kinase C strengthens the evidence for a general role of protein kinase C in proliferation. Yet, the exact consequences of stimulation of protein kinase C in regard to specific proliferation proteins is still not clear. In this study, we present evidence that protein kinase C activation is directed to production of IL-2 but not to IL-2 receptors. Under conditions of TPA treatment in which protein kinase C was chronically reduced in T lymphocytes, IL-2 production was greatly depressed as were the level of IL-2 mRNA and [3H]thymidine incorporation. In contrast, these cells still expressed high affinity IL-2 receptors and proliferated when endogenous IL-2 was added. Because neither phosphatidylinositol metabolism nor Ca2+ flux was affected, the block appeared to be mediated directly or indirectly through protein kinase C.
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PMID:Negative regulation of interleukin-2 production in primary lymphocytes by 12-O-tetradecanoylphorbol-13-acetate. 171 61

Na(+)-Ca2+ exchange contributes to regulation of cytosolic free Ca2+ levels ([Ca2+]i) of cultured human mesangial cells following phospholipase C stimulation, as shown by larger responses to vasoconstrictors such as angiotensin II (ANG II) or endothelin 1 in Na(+)-free media. In turn, previous activation of phospholipase C by vasoconstrictors significantly enhances the amplitude of the [Ca2+]i elevation induced by Na+ withdrawal. We studied the mechanisms of upregulation in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe fura-2. The exchanger was stimulated by insulin and inhibited by chronic exposure to serum. A rise of [Ca2+]i was not sufficient per se to enhance exchange activity, as prior elevation of [Ca2+]i with the ionophores ionomycin or 8-bromo-A23187 failed to augment the response to Na+ withdrawal. Protein kinase C (PKC) activation by phorbol 12-myristate-13-acetate (PMA), alone or in combination with a rise of [Ca2+]i, potently inhibited basal and vasoconstrictor-enhanced Na(+)-Ca2+ exchange. Suppression of the effects of ANG II was not due to frustrated phospholipase C activation by PMA, because addition of PMA after ANG II also inhibited Na(+)-Ca2+ exchange. PKC downregulation by 24-h pretreatment with PMA or inhibition with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine or staurosporine did not prevent activation by ANG II. The exchanger was markedly potentiated by Na+ loading the cells with gramicidin D or reducing extracellular K+. ANG II failed to stimulate Na(+)-Ca2+ exchange when added in the absence of extracellular Na+. Therefore vasoconstrictors promote Na(+)-Ca2+ exchange by a mechanism independent of [Ca2+]i and PKC while presumably linked to Na+ influx.
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PMID:Regulation of Na(+)-Ca2+ exchange in cultured human mesangial cells. 171 60


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