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)

In a previous report we demonstrated the presence of a vasotocin (AVT)-like peptide in chromaffin cells of the amphibian adrenal gland and showed that synthetic AVT is a potent stimulator of corticosterone and aldosterone secretion by frog adrenocortical cells. In the present study we evaluated the relative potency of various AVT analogs and investigated the mechanism of action of AVT on frog interrenal (adrenal) tissue. Several AVT agonists, including hydrin 2, oxytocin (OXT), arginine vasopressin (AVP), Lys-conopressin G, and mesotocin (MT), were able to mimic the stimulatory effect of AVT on steroid secretion, but AVT was by far the most potent stimulator of steroidogenesis. In the series of analogs studied, the order of potency was: AVT greater than hydrin 2 greater than OXT greater than AVP greater than Lys-conopressin G greater than MT greater than [deamino-Cys1,D-Arg8]AVP greater than [d(CH2)5,Tyr(OMe)2] AVP. The effect of AVT (5 x 10(-10) M) was totally blocked by both the antidiuretic V2 antagonist [d(CH2)5,D-Phe2,Ile4,Ala9-NH2]AVP (10(-6) M) and the oxytocinergic antagonist [d(CH2)5,Tyr(OMe)2,Orn8]AVT (10(-6) M); the V2 antagonist was approximately twice as potent as the OXT antagonist. In contrast, the V1 antagonist 1-(1-mercapto-4-phenylcyclohexaneacetic acid)-AVP (10(-6) M) did not affect the response of the interrenal tissue to AVT. Indomethacin (5 microM), a cyclooxygenase inhibitor, induced a dramatic decrease in the spontaneous secretion of corticosteroids, but did not impair the stimulatory effect of AVT (5 x 10(-9) M) on corticosterone and aldosterone secretion. In addition, AVT did not stimulate the production of prostaglandin E2, suggesting that prostaglandins are not involved in the mechanism of action of AVT. Concurrently, AVT did not modify cAMP production by frog adrenal slices. In contrast, AVT induced both an increase in inositolphosphate production and a reduction of membrane phospholipid content. We conclude that in the frog adrenal gland, the stimulatory effect of AVT on steroid secretion is mediated through activation of receptors related to the mammalian V2 and/or OXT receptors, which are positively coupled to phosphoinositide-specific phospholipase C.
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PMID:Pharmacological characterization of vasotocin stimulation of phosphoinositide turnover in frog adrenal gland. 130 45

Recruitment of inflammatory cells to the lung capillaries has been proposed as an important step in the sequence of events that lead to acute lung injury. Frequently, in the clinical setting, bacteremia and sepsis syndrome precede the acute lung failure and endotoxin priming may represent a comparable paradigm, useful for experimental pursuit. Following addition of the chemotactic tripeptide FMLP (10(-9) to 10(-6) M) to the cell-free, salt solution perfusate of isolated rat lungs, only a small degree of vasoconstriction was observed. However, in lungs isolated from rats that received 2 mg/kg intraperitoneal Salmonella enteritidis endotoxin 2 h before lung perfusion, FMLP dose dependently caused a large, transient pulmonary pressor response, edema formation, and release of large amounts of thromboxane and leukotriene B4. Since in vitro priming with endotoxin, direct vascular injury by neutrophil elastase, nor direct stimulation with FMLP of pulmonary artery rings from endotoxin-pretreated rats, mimicked the effects of in vivo endotoxin priming, we conclude that the presence of inflammatory cells in the lung capillaries accounted for the large amount of eicosanoids produced by the lungs after FMLP stimulation. In fact, by retrograde lavage of the lung circulation with a collagenase solution, previously adherent cell clumps were mobilized and identified. These cell clumps, composed of red blood cells, neutrophils, and platelets, were not seen in the vascular lavage sediment obtained from unprimed control lungs. Indomethacin, a thromboxane antagonist, AA861, a 5-lipoxygenase inhibitor, and WEB 2086, a platelet-activating factor (PAF) antagonist, reduced the thromboxane synthesis and release after FMLP (10(-7) M) in in vivo endotoxin-primed lungs. None of the inhibitors employed exclusively inhibited only one particular eicosanoid mediator but rather affected the release of several mediators, suggesting a close link between the different synthetic arachidonic acid pathways. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), NCDC, but not an inhibitor of phospholipase D (Wortmannin) or of protein kinase C (staurosporine) inhibited the FMLP-stimulated pulmonary pressure rise and eicosanoid release in endotoxin-primed lungs in vivo. Our data suggest that eicosanoids (in particular thromboxane) released from cells trapped in the lung circulation, but not from constitutive lung cells, contribute to vasoconstriction and edema formation caused by the chemoattractant FMLP in endotoxin-primed lungs.
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PMID:FMLP causes eicosanoid-dependent vasoconstriction and edema in lungs from endotoxin-primed rats. 154 53

We have previously shown that stimulation of the Ti/CD3 receptor complex on human T-cells potentiates adenylate cyclase activation by adenosine or forskolin. Anti-CD2 receptor antibodies shared with anti-CD3 antibodies the ability to potentiate dose dependently the adenosine- and forskolin-stimulated cyclic adenosine monophosphate (cAMP) accumulation, whereas stimulation of the CD45 receptor had no effect on cyclase activity. Modulation of the CD3 complex with anti-CD3 antibodies was found to decrease the CD2 receptor effect on adenylate cyclase activity greatly. The possible involvement of CD3-stimulated phospholipase C (PLC) activation on the cAMP potentiation was examined using HPB-ALL cells that express a CD3 complex with a defect coupling to PLC. Stimulation of the CD3 complex on HPB-ALL cells had only slight effects on adenosine-stimulated cAMP formation, whereas the effect on forskolin-stimulated cAMP was virtually unchanged. The CD3 effect was further analyzed in Jurkat cell membranes. In contrast to the results obtained after stimulation of intact cells, it was found that OKT3 stimulation of membranes did not potentiate the forskolin response. Finally, we tested whether inhibition of endogenous adenylate cyclase agonist production affected the CD3 effect. Inhibition of adenosine production or adenosine breakdown with 8-p-sulphophenyl theophylline (8-PST) or adenosine deaminase (ADA), respectively, did not alter the CD3 effects. Indometacin, which inhibits prostaglandin production, also had no effect. Together, these data show that stimulation of the CD2 receptor potentiates adenylate cyclase responses by a mechanism that is dependent on CD3 expression. Furthermore, the CD3 effect on cAMP appears to be mediated by two different mechanisms, one which is, and one which is not dependent on PLC. Finally, this effect is not due to an endogenous production of adenylate cyclase agonists.
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PMID:CD3-dependent increase in cyclic AMP in human T-cells following stimulation of the CD2 receptor. 167 13

The hypothesis that von Willebrand factor (vWF) binding to platelet membrane glycoprotein Ib (GpIb) initiates intracellular pathways of platelet activation was studied. We measured the biochemical responses of intact human platelets treated with ristocetin plus vWF multimers purified from human cryoprecipitate. vWF plus ristocetin causes the breakdown of phosphatidylinositol 4,5-bisphosphate, the production of phosphatidic acid (PA), the activation of protein kinase C (PKC), increase of ionized cytoplasmic calcium ([Ca2+]i), and the synthesis of thromboxane A2. PA production, PKC activation, and the rise of [Ca2+]i stimulated by the ristocetin-induced binding of vWF multimers to platelets are inhibited by an anti-GpIb monoclonal antibody, but are unaffected by anti-GpIIb-IIIa monoclonal antibodies. Indomethacin also inhibits these responses without impairing platelet aggregation induced by vWF plus ristocetin. These results indicate that vWF binding to platelets initiates specific intraplatelet signaling pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent activation of phospholipase C after vWF binding to platelet membrane GpIb. This signal then causes PKC activation and increases of [Ca2+]i, which promote platelet secretion and potentiate aggregation.
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PMID:von Willebrand factor binding to platelet GpIb initiates signals for platelet activation. 193 45

Ethanol is known to inhibit the activation of platelets in response to several physiological agonists, but the mechanism of this action is unclear. The addition of physiologically relevant concentrations of ethanol (25-150 mM) to suspensions of washed human platelets resulted in the inhibition of thrombin-induced secretion of 5-hydroxy[14C]tryptamine. Indomethacin was included in the incubation buffer to prevent feedback amplification by arachidonic acid metabolites. Ethanol had no effect on the activation of phospholipase C by thrombin, as determined by the formation of inositol phosphates and the mobilization of intracellular Ca2+. Moreover, ethanol did not interfere with the thrombin-induced formation of diacylglycerol or phosphatidic acid. Stimulation of platelets with phorbol ester (5-50 nM) resulted in 5-hydroxy[14C]tryptamine release comparable with those with threshold doses of thrombin. However, ethanol did not inhibit phorbol-ester-induced secretion. Ethanol also did not interfere with thrombin- or phorbol-ester-induced phosphorylation of myosin light chain (20 kDa) or a 47 kDa protein, a known substrate for protein kinase C. By electron microscopy, ethanol had no effect on thrombin-induced shape change and pseudopod formation, but prevented granule centralization and fusion. The results indicate that ethanol does not inhibit platelet secretion by interfering with the activation of phosphoinositide-specific phospholipase C or protein kinase C by thrombin. Rather, the data demonstrate an inhibition of a Ca2(+)-mediated event such as granule centralization.
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PMID:Ethanol inhibits thrombin-induced secretion by human platelets at a site distinct from phospholipase C or protein kinase C. 211 42

Much evidence indicates that human tissues produce prolactin. However, little is known as to which agents regulate its production in decidual tissues. Therefore, it is of interest to examine the effect of arachidonic acid on the production of prolactin, since it is present in considerably large amounts in decidual tissues. The addition of arachidonic acid to culture media resulted in a significant reduction in the amount of prolactin secreted from incubated decidual tissues in a dose-related fashion. Other poly-unsaturated fatty acids, i.e. linoleic and gamma-linolenic acid also inhibited its secretion, whereas saturated fatty acid and mono-unsaturated fatty acids, such as oleic acid, were without effect. The addition of phospholipase A2 and phospholipase C, enzymes to liberate arachidonic acid from phospholipids, also suppressed the secretion of prolactin. Indomethacin and BW-755C, inhibitors of cyclooxygenase and lipoxygenase, respectively, had essentially no effect on the secretion of prolactin. Translatable mRNA for prolactin was detected in decidual tissues. Arachidonic did not alter either the amount of mRNA in prolactin of the amount of its mRNA as a percentage of total mRNA. Thus, it appears that arachidonic acid possibly plays a role as a physiological regulator of prolactin secretion in human decidual tissues. The action of arachidonic acid is not mediated by cyclooxygenase or lipoxygenase products, suggesting that arachidonic acid itself, or its metabolites other than prostaglandin and leukotriene, may be involved in the regulation of prolactin secretion.
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PMID:[Inhibitory effect of arachidonic acid on the synthesis of prolactin in human decidual tissues]. 212 23

Bombesin is a potent mitogen for Swiss 3T3 cells and can stimulate DNA synthesis in the absence of any other growth factor. This effect is mediated by multiple synergistic signaling pathways, including an accumulation of intracellular cyclic AMP (cAMP) and an increase in c-fos mRNA expression. The cyclooxygenase inhibitor indomethacin abolished prostaglandin E2 release and substantially depressed cAMP levels induced by bombesin (EC50 congruent to 10 nM). In contrast, indomethacin at 1 microM did not affect 80K phosphorylation or Ca2+ mobilization by bombesin, indicating that cAMP synthesis can occur through a phospholipase C-independent pathway. Indomethacin caused a 30 to 35% decrease in c-fos induction and DNA synthesis in cells treated with bombesin (EC50 congruent to 40 nM). Significantly, the inhibitory effect of indomethacin was reversed in the presence of forskolin, a direct activator of adenylate cyclase. We conclude that cAMP plays a regulatory role in c-fos induction and mitogenesis in Swiss 3T3 cells treated with bombesin.
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PMID:Bombesin stimulation of c-fos expression and mitogenesis in Swiss 3T3 cells: the role of prostaglandin E2-mediated cyclic AMP accumulation. 217 Jan 55

In rat membranous nephropathy, formation of the C5b-9 membrane attack complex (MAC) leads to proteinuria in association with glomerular visceral epithelial cell (GEC) injury. These alterations in GEC function and morphology might result from changes in intracellular free Ca2+ concentration [( Ca2+]i) and activation of phospholipases. We demonstrate that in cultured rat GEC, antibody-directed formation of noncytolytic amounts of the MAC induced a rapid and sustained increase in [Ca2+]i that was partly inhibited by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). The MAC elevated levels of inositol bis- (IP2) and trisphosphate (IP3), as well as 1,2-diacylglycerol (DAG) and phosphatidic acid (PA). In permeabilized GEC, IP3 released Ca2+ from intracellular stores. Cellular 45Ca2+ uptake was also increased by the MAC. Thus, in GEC, the MAC induced Ca2+ mobilization from intracellular stores secondary to activation of phospholipase C and production of IP3, as well as enhanced Ca2+ influx. In addition, C5b-9 stimulated release of arachidonic acid (AA), prostaglandin F2 alpha, and thromboxane A2. Indomethacin partially inhibited the increase in DAG levels observed with the MAC, whereas the prostaglandin H2/thromboxane A2 analogue U46619 elevated DAG, suggesting that an eicosanoid product of MAC-induced AA release may enhance the activation of phospholipase C. Activation of phospholipases by the MAC may lead to altered GEC function and thereby contribute to the pathophysiological changes that characterize complement-dependent rat membranous nephropathy.
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PMID:Complement C5b-9 complex activates phospholipases in glomerular epithelial cells. 251 64

Serotonin (5-HT), histamine (HA), angiotensin II (ATII), prostaglandin F2 alpha (PGF2 alpha) and thromboxane A2 (TxA2) are known as vasoactive substances, each producing a characteristic contraction of cerebral arteries. These contractions are considered to be mediated by their specific receptors. Recent studies suggest that the activations of these receptors primarily stimulate the phospholipase C and/or phospholipase A2 localized within the same membrane. Stimulation of these enzymes consequently induces production of the second or third messengers such as inositol triphosphate (IP3), diacylglyceride (DAG), arachidonic acid (AA), and ultimately various prostaglandins. The present study is to examine how oxyhemoglobin (Oxy-Hb), another vasoactive substance, can modify these receptor-mediated contractions, and to compare the effects on high K+-, caffeine-and 1-oleoyl-2-acetyl-rac-glycerol (OAG)-induced contractions which are not mediated by the receptors on the cytoplasmic membrane. Helical strips of the bovine middle cerebral arteries (M2) were mainly used in this experiment, and the changes in muscular tensions during isometric contractions were recorded on the polygraph. 5-HT, HA, ATII, PGF2 alpha and cTxA2 (carbocyclic thromboxane A2) were used for each receptor activation. Indomethacin (IDM), a cyclooxygenase inhibitor and 2-nitro-4-carboxyphenyl-n, n-diphenyl-carbamate (NCDC), a phospholipase C inhibitor were used to analyze a possible acting site of Oxy-Hb in modifying these reseptor-mediated enzyme reactions. The results obtained are summarized as follows. (1) All contractions induced by either 5-HT, PGF2 alpha, cTxA2, HA or ATII (concentrations less than 10(-6) M) were markedly augmented as much as 4-8 times the normal, when they were examined in the presence of 10(-5)M Oxy-Hb.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Selective augmenting effect of oxy-Hb on the contractions of cerebral arteries elicited by various vasoactive substances]. 290 26

Twelve Staphylococcus aureus strains, six positive and six negative for delta-toxin production, were studied for synergistic effects on mouse mortality and morbidity when combined with Candida albicans and inoculated intraperitoneally (i.p.). S. aureus strains producing delta-toxin were found to exhibit a relatively great synergistic decrease (between near 10(3)-10(5)-fold) in LD50 (dose necessary to kill 50% of exposed animals in five days) when combined with a nonlethal dose of C. albicans and injected i.p. S. aureus strains which did not produce delta showed less of a synergistic effect with C. albicans (10-10(2)-fold drop in LD50). A synergistic effect on mortality could also be produced when animals were dually injected with C. albicans and sterile growth filtrates from the delta-toxin producing strains or the purified delta-toxin. The lethal agent in the culture filtrate was, like delta-toxin, sensitive to lecithin and insensitive to heat. Indomethacin protected animals from the C. albicans-filtrate induced death. Blood measurements made following i.p. injection of delta-toxin and C. albicans revealed chemistry changes indicative of shock, kidney and liver damage; delta-toxin alone caused no significant chemistry changes whereas C. albicans alone caused some blood chemistry changes but liver and kidney damage was not indicated. No synergism on mortality was found between C. albicans and purified alpha-toxin or toxic shock syndrome toxin-1.
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PMID:Synergism of Candida albicans and delta toxin producing Staphylococcus aureus on mouse mortality and morbidity: protection by indomethacin. 306 97


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