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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of membrane phospholipids in porcine testicular androgen and 16-androstene biosynthesis was examined by monitoring the effects of phospholipase treatments on the activities of the steroid transforming enzymes. Untreated (control) microsomes from immature pig testes converted pregnenolone to 17-hydroxypregnenolone and DHA to 5,16-androstadien-3 beta-ol (andien-beta) and 4,16-androstadien-3-one (dienone) in the 16-androstene pathway, these metabolites accounting for most (65%) of the pregnenolone converted. The 4-ene steroids in the androgen pathway (progesterone, 17-hydroxyprogesterone, androstenedione and testosterone) totalled less than 10% of the pregnenolone metabolites. No estrogens or 5 alpha-reduced metabolites were detected. Treatment with phospholipase A2 or C, decreased the conversion of pregnenolone to 4-ene-3-oxo steroids but did not decrease the quantities of 5-ene-3 beta-hydroxysteroids. Confirmation of these findings was obtained by measuring the individual enzymatic steps. Phospholipases A2 and C significantly reduced the conversion of DHA to androstenedione and andien-beta to dienone but did not affect 17-hydroxylase or 'andien-beta-synthetase'. However, when the C-17, 20 lyase step was measured alone, phospholipase C decreased the quantity of androstenedione produced indicating that the side-chain cleavage reaction may involve a lipid component. The different effects of phospholipases on these enzymes suggests that pregnenolone metabolism may be regulated by alterations in the membrane microenvironment.
J Steroid Biochem Mol Biol 1992 Jan
PMID:Phospholipases modulate immature pig testicular androgen and 16-androstene biosynthetic pathways in vitro. 173 40

Prolactin (PRL) induces liberation of arachidonic acid (AA) from phospholipids of lactating mammary epithelial cells and stimulates casein secretion. In order to investigate the possible involvement of phospholipase A2 (PLA2) activity in the hormonal control of casein secretion by PRL, we examined the effects of crotoxin, a PLA2 neurotoxin from snake venom, on mammary epithelial cells. Crotoxin is made of two subunits: a basic PLA2 with low toxicity (component B, CB) and an acidic, non-toxic and enzymatically inactive component A (CA) which enhances the pharmacological action of CB. While CA is inactive, the PLA2 subunit (CB) induces an accumulation of secretory products in the lumen of mammary acini, an extensive development of the Golgi apparatus. The secretion of newly synthesized casein is increased in the presence of CB and this effect is inhibited by nordihydroguaiaretic acid (NDGA) and caffeic acid, two inhibitors of the lipoxygenase pathway which also prevent stimulation of secretion by PRL. Further, CB transiently induces the release of radiolabelled AA from mammary tissues previously labelled with [14C]AA, the highest release being observed between 15 s and 5 min of contact with CB and CA. Immunofluorescence labelling by anti-CB antibodies of epithelial mammary tissues previously incubated with CA, CB or a combination of CA and CB indicates that CB binds to epithelial cells and is internalized, at least in part, and that CA enhances both CB binding and its internalization. These observations emphasize the involvement of PLA2 in the control of casein secretion and suggest that PLA2 acts intracellularly.
Mol Cell Endocrinol 1991 Nov
PMID:Crotoxin, a phospholipase A2 neurotoxin from snake venom, interacts with epithelial mammary cells, is internalized and induces secretion. 176 Nov 65

Diethylcarbamazine (DEC) rapidly lowers the number of microfilariae in the peripheral circulation. The mechanism of action is unknown, but may involve alterations of arachidonic acid metabolism in vascular tissues. We studied the effects of DEC on arachidonic acid metabolism by bovine pulmonary arterial endothelium monolayers, human platelets and Brugia malayi microfilariae. DEC at a concentration of 2.5 microM, a level achieved in vivo, rapidly decreased prostacyclin, prostaglandin E2 and thromboxane B2 release from endothelial monolayers by 78% (P less than 0.001), 57% (P = 0.05), and 75% (P less than 0.05), respectively. High-pressure liquid chromatography of extracts of endothelial monolayers incubated with DEC showed similar inhibition of these cyclooxygenase pathway products, but exposure to the drug did not result in formation of new eicosanoids. DEC did not inhibit endothelial phospholipase A2-dependent release of arachidonate from membrane stores, whereas prostaglandin H2 synthase activity (cyclooxygenae, EC 1.14.99.1) was reduced to a degree similar to that effected by acetylsalicylic acid. Microfilarial but not platelet synthesis of cyclooxygenase products was also reduced by DEC. These data suggest that the mechanism by which DEC lowers the level of microfilariae in the circulation may in part involve its effects on host endothelial and parasite eicosanoid production.
Mol Biochem Parasitol 1991 Nov
PMID:Diethylcarbamazine inhibits endothelial and microfilarial prostanoid metabolism in vitro. 177 51

Human peripheral blood monocytes synthesize the potent lipid autacoid platelet-activating factor (PAF) following appropriate stimulation. We examined the role of protein kinase C (PKC) in regulating the synthesis of PAF by stimulated monocytes. 4 beta-phorbol 12-myristate 13-acetate (PMA) and 1,2-dioctanoyl-sn-glycerol, which directly activate PKC, stimulated the synthesis of PAF. Sphingosine, a long-chain amine that inhibits PKC, blocked both the binding of phorbol esters to monocytes and the synthesis of PAF in response to PMA (half-maximal inhibition at 5 to 10 microM and complete inhibition at 10 to 30 microM sphingosine). Thus, the activation of PKC was necessary and sufficient for PAF synthesis in response to phorbol ester. Sphingosine also blocked PAF synthesis in response to the calcium ionophore A23187 and opsonized zymosan particles by specific inhibition of PKC. Two other PKC inhibitors, stearylamine and staurosporine, also blocked PAF synthesis following A23187 or opsonized zymosan stimulation. These experiments demonstrated that PKC activation was required for PAF synthesis in response to the calcium signal generated by A23187 or a receptor-mediated agonist, opsonized zymosan. The synthesis of PAF and leukotriene B4 were temporally coupled following cell stimulation. Further, production of these two lipid mediators, and the release of arachidonic acid, were inhibited in parallel by sphingosine. Thus, PKC regulate the synthesis of both PAF and leukotriene B4 at a common step, probably phospholipase A2.
Am J Respir Cell Mol Biol 1991 Feb
PMID:Protein kinase C regulates the synthesis of platelet-activating factor by human monocytes. 184 46

The effect of alpha 2-adrenergic receptor activation on adenylate cyclase activity in Chinese hamster ovary cells stably transfected with the alpha 2A-adrenergic receptor gene is biphasic. At lower concentrations of epinephrine forskolin-stimulated cyclic AMP production is inhibited, but at higher concentrations the inhibition is reversed. Both of these effects are blocked by the alpha 2 antagonist yohimbine but not by the alpha 1 antagonist prazosin. Pretreatment with pertussis toxin attenuates inhibition at lower concentrations of epinephrine and greatly potentiates forskolin-stimulated cyclic AMP production at higher concentrations of epinephrine. alpha 2-Adrenergic receptor stimulation also causes arachidonic acid mobilization, presumably via phospholipase A2. This effect is blocked by yohimbine, quinacrine, removal of extracellular Ca2+, and pretreatment with pertussis toxin. Quinacrine and removal of extracellular Ca2+, in contrast, have no effect on the enhanced forskolin-stimulated cyclic AMP production. Thus, it appears that the alpha 2-adrenergic receptor in these cells can simultaneously activate distinct signal transduction systems; inhibition of adenylate cyclase and stimulation of phospholipase A2, both via G1, and potentiation of cyclic AMP production by a different (pertussis toxin-insensitive) mechanism.
Mol Pharmacol 1991 Feb
PMID:Alpha 2-adrenergic receptor stimulation of phospholipase A2 and of adenylate cyclase in transfected Chinese hamster ovary cells is mediated by different mechanisms. 184 97

Epidermal growth factor (EGF) acts on various cell types, including the mouse Leydig tumor cell line MA-10, where it has been shown to stimulate steroidogenesis, apparently in a cAMP-independent manner. In the process of examining other possible signaling pathways for EGF in these cells, we found rapid changes in the intracellular concentration of arachidonic acid (AA) following addition of EGF. For example, a significant increase in AA was detected 1 min after incubating the cells with EGF, with the maximal effect observed at an EGF concentration of 10 ng/ml. In addition, exogenous AA increased steroidogenesis, and the steroidogenesis enhanced by AA and EGF was reduced by lipoxygenase inhibitors, suggesting a possible role of an AA metabolite(s) in promoting steroidogenesis. Consistent with this hypothesis is our observation that several exogenous lipoxygenase metabolites were capable of enhancing progesterone production. The EGF-stimulated steroidogenesis was also inhibited by two phospholipase A2 inhibitors, again confirming a probable role of AA or a metabolite in this process. Therefore, AA appears to be an important intracellular mediator responsible, at least in part, for some of the acute metabolic effects mediated by EGF in MA-10 cells.
Mol Cell Endocrinol 1991 Mar
PMID:Epidermal growth factor modulates intracellular arachidonic acid levels in MA-10 cultured Leydig tumor cells. 185 Nov 14

Triethyl lead chloride (Et3PbCl) was found to induce a shift of fatty acids from membrane phospholipids to triacylglycerols in the human promyelocytic leukemia cell line HL-60. High concentrations of Et3PbCl (greater than 10 microM) caused a substantial liberation of [14C]arachidonic acid within 10 to 20 min in dimethyl sulfoxide-differentiated cells, comparable to the effect of the calcium ionophore A23187 (10 microM). Following liberation of arachidonic acid, its metabolites could be detected. Prolongation of the incubation time and reduction of Et3PbCl concentration resulted in a shift of fatty acids from phospholipids to triacylglycerols. Deacylation of phospholipids and reacylation into phospholipids and triacylglycerols were in equilibrium when the cells were treated with Et3PbCl at concentrations of less than or equal to 10 microM for 5 hr or less than or equal to 1 microM for 24 hr; no increase of free fatty acids could be observed, and the loss of fatty acids within the phospholipids was equivalent to the increase of fatty acid content within the triacylglycerols. Moreover, under these conditions, no loss of viability was seen after 24 hr, as compared with untreated differentiated cells. This concentration- and time-dependent effect of Et3PbCl might be due to a stimulated liberation of fatty acids via phospholipase A2, because this stimulation could be totally prevented by the phospholipase inhibitors quinacrine and p-bromophenacylbromide. Additionally, pretreatment of differentiated HL-60 cells with pertussis toxin resulted in a drastic reduction of [14C]arachidonic acid liberation when cells were stimulated with Et3PbCl. These results suggest the involvement of a pertussis toxin-sensitive GTP-binding protein and of a signal transduction mechanism during stimulated fatty acid release; release does not seem to be via a direct stimulation of phospholipase activity by the lead compound.
Mol Pharmacol 1991 Apr
PMID:Directed shift of fatty acids from phospholipids to triacylglycerols in HL-60 cells induced by nanomolar concentrations of triethyl lead chloride: involvement of a pertussis toxin-sensitive pathway. 190 39

Cadmium exposure is capable of causing acute and chronic lung injuries, but the specific pathogenetic mechanisms are uncertain. The effects of cadmium ion (Cd2+) on phospholipid metabolism were examined in cultured bovine pulmonary artery endothelial cells (BPAEC), as endothelial cells appear to be particularly vulnerable to the toxic effects of this metallic ion. Exposure of radiolabeled BPAEC to millimolar concentrations of Cd2+ causes liberation of substantial amounts of [3H]arachidonic acid ([3H]AA), but only small amounts of [14C]stearic acid, from each of the major phospholipid subclasses. Analyses of hydrolytic products in BPAEC radiolabeled with [3H]myo-inositol and exposed to Cd2+ indicate that degradation of complex phospholipids is mediated by phospholipase A2. The ability of BPAEC to incorporate fatty acids or lysophosphatides into complex phospholipids is similarly impaired after exposure to Cd2+, suggesting that the liberation of [3H]AA might be due to impairment of reacylation mechanisms and not to increased hydrolytic activity of phospholipase A2. Of the two enzymes involved in reacylation reactions, Cd2+ is found to inhibit the activity of arachidonyl-specific acyl coenzyme A synthetase but not the activity of acyltransferase. Cd2+ also causes a profound time- and dose-dependent depletion of adenosine triphosphate levels in BPAEC, and these changes closely correlate with the liberation of [3H]AA. We suggest that impairment of reacylation mechanisms, and the consequent accumulation of arachidonic acid, may be important in the development of the acute inflammatory reaction that is characteristic of Cd(2+)-induced lung injury.
Am J Respir Cell Mol Biol 1991 Oct
PMID:Cadmium ion-induced alterations of phospholipid metabolism in endothelial cells. 191 Aug 17

Gonadotropin (GTH) release in static incubations of dispersed goldfish pituitary cells was stimulated by chicken GTH-releasing hormone II (cGnRH-II), salmon (s)GnRH, phospholipase A2, phospholipase C, phospholipase D, and arachidonic acid (AA). Coincubations with nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraenoic acid, and indomethacin did not alter the GTH responses to cGnRH-II. In contrast, NDGA reduced sGnRH-stimulated GTH release. Incubation with Ca(2+)-deficient medium abolished the GTH responses to cGnRH-II, reduced sGnRH-stimulated GTH release, but did not alter AA actions on GTH secretion. Apomorphine, a dopamine agonists that had been shown to partially inhibit the GTH responses to sGnRH and to abolish those induced by cGnRH-II, did not affect the hormone response to AA. However, the partial inhibitory actions of NDGA and apomorphine on sGnRH-induced GTH release were additive. These findings suggest the existence of a major difference in cGnRH-II and sGnRH stimulation of GTH release--AA metabolism is not involved in cGnRH-II, as opposed to sGnRH actions. This difference in second messenger activation may also explain the differential sensitivity of the two GnRH peptides to dopamine inhibition and manipulations of extracellular Ca2+ availability. The results further suggest that dopamine and AA affect GTH release via non-overlapping signal transduction pathways.
Mol Cell Endocrinol 1991 Aug
PMID:Lack of involvement of arachidonic acid metabolism in chicken gonadotropin-releasing hormone II (cGnRH-II) stimulation of gonadotropin secretion in dispersed pituitary cells of goldfish, Carassius auratus. Identification of a major difference in salmon GnRH and chicken GnRH-II mechanisms of action. 193 48

This study evaluates the role of intracellular levels of Ca2+ [Ca2+]i in cyclic GMP formation mediated by muscarinic and histamine receptors in the mouse neuroblastoma clone N1E-115. Muscarinic agonists activated the turnover of phosphoinositides with a relative maximal response similar to that observed previously for cyclic GMP formation. Carbamylcholine induced a transient increase in inositol trisphosphate with a time course similar to that of cyclic GMP formation. In cells loaded with the fluorescent Ca2+ probe fura-2/acetoxymethyl ester, carbamylcholine as well as histamine induced a rapid and transient rise in [Ca2+]i. The time course of the changes in [Ca2+]i induced by agonists as well as by ionomycin closely paralleled that of cyclic GMP formation. Chelation of [Ca2+]i by loading of N1E-115 cells with quin 2/acetoxymethyl ester inhibited cyclic GMP formation induced by agonists in a dose-dependent manner. When cyclic GMP formation induced by agonists was assayed after the cells were exposed to 3 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) for 2 min, the formation of cyclic GMP was not inhibited significantly; however, it was completely abolished after 30-min exposure to EGTA. Treatment of cells with phospholipase A2 had no effect on resting [Ca2+]i and only slightly increased cyclic GMP formation, in spite of the induction of a marked release of [3H]arachidonate. Moreover, the formation of cyclic GMP induced by ionomycin was inhibited by the addition of phospholipase A2. Melittin contaminated with phospholipase A2 activity induced a rapid and sustained increase in cyclic GMP formation, as well as unesterified [3H]arachidonate release. However, after inactivation of the phospholipase A2 activity of melittin, its ability to stimulate cyclic GMP formation was enhanced. Our data indicate that receptor agonists stimulate cyclic GMP formation in N1E-115 cells by activating the formation of inositol trisphosphate, which is followed by the release of Ca2+ from intracellular stores. The evidence obtained does not support a major role for arachidonate release in receptor-mediated activation of guanylate cyclase. Conversely, it is consistent with an inhibitory role for arachidonic acid or its metabolites in this process.
Mol Pharmacol 1990 Jun
PMID:Role of intracellular Ca2+ mobilization in muscarinic and histamine receptor-mediated activation of guanylate cyclase in N1E-115 neuroblastoma cells: assessment of the arachidonic acid release hypothesis. 197 74


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