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:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebellar neurons, cultured on monolayers of 3T3 fibroblasts or on a polylysine/laminin-coated substratum, responded to recombinant basic FGF by extending longer neurites. The response was biphasic reaching a maximum at 5 ng/ml FGF, but desensitising at 100-200 ng/ml FGF. The response to FGF could be inhibited by a tyrosine kinase inhibitor (the erbstatin analogue), by a diacylglycerol lipase inhibitor (RHC-80267) and by a combination of N- and L-type calcium channel antagonists or other agents that negate the effects of calcium influx into neurons. The response to FGF could be fully mimicked by arachidonic acid added directly to the cultures, or generated via activation of phospholipase A2 with melittin. The response to melittin, but not to FGF or arachidonic acid, was inhibited by 4-bromophenacyl bromide, a phospholipase A2 inhibitor. The response to arachidonic acid was also biphasic and high concentrations of this agent could cross-desensitise the FGF response and vice versa. The response to arachidonic acid could be fully inhibited by the agents that block or negate the effects of calcium influx into neurons, but was not inhibited by the tyrosine kinase or diacylglycerol lipase inhibitors. These data suggest that FGF stimulates neurite outgrowth by activating a cascade that involves activation of phospholipase C gamma to produce diacylglycerol, conversion of diacylglycerol to arachidonic acid by diacylglycerol lipase and the activation of voltage-gated calcium channels by arachidonic acid.
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PMID:Characterisation of the second messenger pathway underlying neurite outgrowth stimulated by FGF. 805 Mar 74

We have used monolayers of control 3T3 fibroblasts and 3T3 fibroblasts expressing transfected cell adhesion molecules (CAMs)--NCAM, N-cadherin, and L1--as a culture substrate for cerebellar neurones. The transfected CAMs promote neurite outgrowth by activating a second messenger pathway that culminates in calcium influx into neurones through N- and L-type calcium channels. We show that the same neurite outgrowth response can be directly induced by arachidonic acid (10 microM) and that this response can be inhibited by N- and L-type calcium channel antagonists. In cells, arachidonic acid can be generated by phospholipase A2 or by the sequential activities of a phospholipase C (to generate diacylglycerol) and diacylglycerol lipase. In the present study we show the neurite outgrowth stimulated by CAMs (but not by various other agents) can be abolished by an inhibitor of diacylglycerol lipase acting at a site upstream from calcium channel activation. The results suggest that arachidonic acid and/or one of its metabolites is the second messenger that activates calcium channels in the CAM signalling pathway leading to axonal growth, and this is supported by recent evidence that shows the same concentrations of arachidonic acid can increase voltage-dependent calcium currents in cardiac myocytes.
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PMID:The production of arachidonic acid can account for calcium channel activation in the second messenger pathway underlying neurite outgrowth stimulated by NCAM, N-cadherin, and L1. 811 7

alpha 1-Adrenergic receptors (ARs) are members of the G protein-coupled receptor superfamily. alpha 1-AR subtypes mediate the effects of the sympathetic nervous system, especially those involved in cardiac homeostasis. To investigate signal transduction by a novel subtype (alpha 1D), which we recently cloned, and to compare it with that by the previously characterized alpha 1B-AR, we assessed the ability of each subtype to activate polyphosphoinositide (PI) metabolism, cAMP accumulation, and arachidonic acid release in Chinese hamster ovary (CHO) and COS-1 cells expressing these subtypes after stable or transient transfection, respectively. In COS-1 and CHO cells, both the alpha 1D- and alpha 1B-AR were found to couple to PI hydrolysis through a pertussis toxin-insensitive G protein. Both alpha 1-AR subtypes also increased intracellular cAMP by an indirect mechanism, although this effect was observed only in COS-1 cells and not in CHO cells. Interestingly, alpha 1-AR-stimulated arachidonic acid release was also demonstrated for both subtypes in COS-1 cells. This release was mediated through phospholipase A2 activation and involved a pertussis toxin-sensitive G protein. alpha 1-AR-stimulated arachidonic acid release was dependent upon extracellular calcium and was inhibited by 1 microM nifedipine. Inhibitors of protein kinase C, phospholipase C, and diacylglycerol lipase did not alter alpha 1-AR-stimulated release of arachidonic acid. These findings indicate that in COS-1 cells alpha 1-AR-stimulated arachidonic acid release is most likely coupled to dihydropyridine-sensitive L-type calcium channels via a pertussis toxin-sensitive G protein. The influx of extracellular calcium then stimulates phospholipase A2 to release arachidonic acid. alpha 1-AR-stimulated arachidonic acid release could also be demonstrated in CHO cells and was pertussis toxin sensitive but nifedipine insensitive. These cells were also unresponsive to Bay K8644, indicating a lack of voltage-sensitive calcium channels in CHO cells. Nevertheless, alpha 1-AR activation increased intracellular Ca2+ levels, as assessed by fura-2 fluorescence studies. Neomycin blocked both alpha 1-AR-stimulated PI hydrolysis and increases in intracellular Ca2+ levels but did not inhibit the increase in arachidonic acid release. Taken together, these data indicate that in CHO cells alpha 1-ARs can couple directly to phospholipase A2 activation via a pertussis toxin-sensitive pathway. Thus, in these model systems we demonstrate for the first time that a single alpha 1-AR subtype can activate multiple distinct signal transduction pathways, in which receptor-effector coupling is modulated by distinct G proteins.
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PMID:Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptor to multiple signaling pathways is both G protein and cell type specific. 823 29

The protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu) induced the release of both luteinizing hormone (LH) and growth hormone (GH) from proestrous rat anterior pituitary pieces in vitro. Phorbol 12,13-dibutyrate-induced LH, but not GH release was readily inhibited by the phospholipase A2 (PLA2) inhibitors, quinacrine, aristolochic acid, ONO-RS-082 and chloracysine. Furthermore, PDBu induced release of [3H]arachidonic acid ([3H]AA) from pre-labelled anterior pituitary tissue that was prevented in the presence of quinacrine, aristolochic acid and ONO-RS-082 but not the diglyceride lipase inhibitor RHC 80267. The effect of PDBu was completely inhibited by staurosporine and the selective PKC inhibitor Ro 31-8220 but only partially by low concentrations of H7; consistent with the involvement of both H7-sensitive and H7-resistant forms of PKC in the activation of PLA2 by PDBu. The protein synthesis inhibitor cycloheximide inhibited the release of both [3H]AA and LH that had been induced by PDBu, whereas LH release induced by the PLA2 activator mellitin was cycloheximide-insensitive. These results suggest that PKC activators may induce LH but not GH release from anterior pituitary tissue by a mechanism involving activation of a PLA2, brought about by a process which is reliant on protein synthesis.
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PMID:Differential involvement of phospholipase A2 in phorbol ester-induced luteinizing hormone and growth hormone release from rat anterior pituitary tissue. 824 10

In the present study, we investigated the mechanism by which bradykinin (BK) enhances [3H]arachidonic acid release in murine osteoblast-like MC3T3-E1 cells prelabeled with [3H]arachidonic acid. BK enhanced [3H]arachidonic acid release in a time- and concentration-dependent manner, when cells were stimulated in the presence, but not in the absence, of extracellular Ca2+. It appears that the BK-induced [3H]arachidonic acid release was attributed to the activation of phospholipase A2, since a phospholipase A2 inhibitor, mepacrine, significantly inhibited the BK enhancement of [3H]arachidonic acid release whereas a diacylglycerol lipase inhibitor, RHC80267, failed to do so. Furthermore, it was found that a protein kinase C inhibitor, staurosporine, and down-regulation of protein kinase C by prolonged exposure of cells to phorbol 12-myristate 13-acetate inhibited the BK-induced [3H]arachidonic acid release. These results provide evidence that BK stimulation of MC3T3-E1 cells activates phospholipase A2 to liberate arachidonic acid by the mechanism which involves both Ca2+ and protein kinase C.
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PMID:The mechanism of bradykinin-induced arachidonic acid release in osteoblast-like MC3T3-E1 cells phospholipase A2 activation by bradykinin and its regulation by protein kinase C and calcium. 826 65

We analyzed de novo synthesis and local turnover of phospholipids in the growing neuron and the isolated nerve growth cone. The metabolism of phosphatidylinositol (PI) was studied with regard to the incorporation of saturated and unsaturated fatty acids and inositol. A comparison of de novo phospholipid synthesis in the intact neuron (whole brain, cell cultures) versus local turnover in isolated growth cone particles (GCPs) from fetal rat brain revealed different incorporation patterns and, in particular, high arachidonic acid (AA) turnover in PI of GCPs. These observations, together with elevated levels of free AA (2.5% of total AA content) in GCPs, demonstrate the predominance of acylation/deacylation in the sn-2 position of PI. GCP phospholipase A2 (PLA2) activity was demonstrated using [3H]-or [14C]AA-phosphatidylcholine (PC) or -PI as the substrate in vitro and GCPs or a cytosolic GCP extract as the source of enzyme. In contrast to PC, which is hydrolyzed very slowly, PI is a very good GCP PLA2 substrate. PLA2 activity is much higher in GCPs than that of phospholipase C, as demonstrated by the comparison of AA and inositol turnover, by the low levels of 1,2-diacylglycerol generated by GCPs, and by the resistance of AA release to treatment of GCPs with RHC-80267, a specific inhibitor of diacylglycerol lipase. The predominance of PLA2 activity in GCPs raises questions regarding its regulation and the functional roles of PI metabolites, especially lysocompounds, in growth cones.
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PMID:Arachidonic acid turnover and phospholipase A2 activity in neuronal growth cones. 843 62

In guinea pig gastric longitudinal (LM) and circular (CM) muscle strips, angiotensin-II (Ang-II) caused a concentration-dependent contraction that required extracellular calcium and that could not be attributed to the secondary release of agonists from neural elements. Contractions in both the LM and CM were blocked by the Ang-II AT1 receptor antagonist, Losartan (DuP 753, pA2 9.1) but not by the AT2 antagonist, PD 123319. However, in the LM preparation, indomethacin (3 microM) blocked Ang-II-mediated contraction, whereas in the CM contraction was resistant to indomethacin. Contractions caused by Ang-II in the CM preparations were also unaffected by inhibitors of leukotriene biosynthesis, but were partially (58%) inhibited by the cytochrome P450 monooxygenase inhibitor, ketoconazole. The diacylglycerol lipase inhibitor, U57,908, at a concentration (20 microM) that completely blocked the contractile action of epidermal growth factor in the LM, caused a substantial inhibition of Ang-II-mediated contraction in both the LM (55% inhibition) and CM (75% inhibition). The phospholipase A2 inhibitor, mepacrine caused a modest inhibition (24%) of contraction in both preparations. In the presence of U57,908, mepacrine further inhibited contraction caused by Ang-II in the LM preparation. The tyrosine kinase (YK) inhibitors, genistein and tyrphostin (RG 50864) selectively and completely blocked Ang-II-mediated contraction in the LM, without affecting contractions caused by carbachol and bradykinin. In the CM preparation, the two YK inhibitors were selective, but only partially (40-60%) blocked Ang-II-mediated contraction, without affecting contractions caused by bradykinin and carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Distinct signal transduction pathways for angiotensin-II in guinea pig gastric smooth muscle: differential blockade by indomethacin and tyrosine kinase inhibitors. 843 35

The inflammatory mediator, adenosine, induces chloride secretion from the human colonic epithelial cell line, T84, in a manner apparently independent of increases in adenosine 3',5'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate, or cytoplasmic Ca2+. This prompted a search for other messengers that might account for the secretory response. A possible role for arachidonic acid or a metabolite in the response to adenosine has been demonstrated 1) by showing a relationship between arachidonic acid mobilization and chloride secretion induced by the adenosine agonist 5'-(N-ethylcarboxamido)adenosine (NECA) and 2) by determining that exogenous arachidonic acid affects T84 cell function. Addition of NECA to T84 cells induces chloride secretion and release of radioactivity from cells preloaded with [3H]arachidonic acid with similar dose dependencies. The effect of NECA on chloride secretion is inhibited by the phospholipase A2 inhibitor 4-bromophenacyl bromide or the diglyceride lipase inhibitor RG80267 but is unaffected by inhibitors of lipoxygenase or cyclooxygenase. Arachidonic acid has a small but significant effect on chloride secretion when added alone to T84 cells and synergistically enhances, as does NECA, responses to calcium-dependent secretogogues. Thus receptor-stimulated release of arachidonic acid in T84 cells may provide a second-messenger system promoting chloride secretion, in addition to calcium and cyclic nucleotides.
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PMID:Involvement of arachidonic acid in the chloride secretory response of intestinal epithelial cells. 844 75

The aim of the present paper was to clarify if the prostaglandin F2 alpha (PGF2 alpha) production stimulated by mammalian gonadotropin-releasing hormone (mGnRH) comes from arachidonic acid (AA) freed by diacylglycerol (DAG) and/or membrane phospholipids in the interrenal of Rana esculenta. Interrenals of Rana esculenta were incubated with inhibitors of phospholipase A1 (PLA1), phospholipase A2 (PLA2), phospholipase C (PLC), protein kinase C (PKC) and diacylglycerol lipase (DAGlipase) in the presence or absence of mGnRH. In parallel, the same experiments were carried out using [3H]AA-labelled interrenals. The results of the experiments with non-labelled and [3H]AA-labelled interrenals were in agreement. PLA1, PLA2, PLC, PKC and DAGlipase inhibitors induced a decrease in PGF2 alpha production in interrenals without mGnRH, and PLA2 inhibitor was more effective than other inhibitors. PLC and DAGlipase inhibitors decreased the PGF2 alpha production by interrenals incubated with mGnRH, and PLC inhibitor was more effective than DAGlipase inhibitor. These findings suggest that the main source of AA used for mGnRH-induced PGF2 alpha synthesis is DAG; probably this decapeptide increases PGF2 alpha production enhancing the DAGlipase activity.
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PMID:Mammalian gonadotropin-releasing hormone increases PGF2 alpha production activating diacylglycerol lipase in Rana esculenta interrenal. 845 54

Some arachidonic acid metabolites might be among the intracellular signalling substances that regulate hormone release. We report that the phospholipase A2 and diacylglycerol lipase inhibitor quinacrine (1-10 mumol l-1) inhibited the thyroliberin stimulated prolactin (rPRL) production in a dose-dependent way in a rat pituitary tumour cell line (GH4Cl cells). The lipoxygenase inhibitor nafazatrom (5-50 mumol-1) also dose-dependently inhibited the thyroliberin stimulated rPRL production, while the cyclo-oxygenase inhibitor indomethacin had no such effect on rPRL production. The inhibitors of the arachidonic acid metabolism (quinacrine, ETYA and nafazatrom) had no effect on the accumulation of inositolpolyphosphates indicating that the arachidonic acid metabolites are not involved in the regulation of the phospholipase C activity.
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PMID:Inhibitors of the arachidonic acid metabolism attenuate the thyroliberin (TRH) stimulated prolactin production without modifying the production of inositolphosphates in GH4C1 pituitary cells. 846 10


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