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)

Two amphiphilic peptides from hymenopterid insects, melittin and mastoparan, stimulate secretion in a variety of cell types. In PC12 cells, both peptides stimulate calcium influx with melittin some 20-fold more potently than mastoparan. Melittin stimulates both breakdown of phosphoinositides (Pl) by phospholipase C to yield inositol phosphates and hydrolysis of phospholipids by phospholipase A2 to release arachidonic acid (AA). Mastoparan stimulates Pl breakdown, but has no effect on AA release. Maximal stimulation of Pl breakdown occurs at 1 to 2.5 micrograms/ml melittin and 30 micrograms/ml mastoparan, whereas maximal stimulation of AA release occurs at 2 to 5 micrograms/ml melittin. Organic calcium channel blockers (nifedipine, verapamil, diltiazem) have little or no effect on responses to the peptides. The influx of calcium elicited by melittin or mastoparan is completely or nearly completely blocked by inorganic calcium channel blockers (Co++, Mn++, Cd++). Mn++ and Cd++ inhibit melittin-induced Pl breakdown and AA release and mastoparan-induced Pl breakdown. Co++ has no effect on melittin-induced Pl breakdown and potentiates mastoparan-induced Pl breakdown. Pertussis toxin has no effect on the Pl breakdown induced by either peptide. The responses to melittin and mastoparan in PC12 cells are compared to those reported for maitotoxin.
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PMID:Effects of the amphiphilic peptides melittin and mastoparan on calcium influx, phosphoinositide breakdown and arachidonic acid release in rat pheochromocytoma PC12 cells. 130 80

DDT1-MF2 smooth muscle cells demonstrated a robust phospholipase C response to norepinephrine, as detected by inositol phosphate accumulation. A selective A1-adenosine receptor agonist, cyclopentyladenosine, caused only a minor stimulation of phospholipase C, which was eliminated in the absence of added extracellular calcium. The simultaneous addition of norepinephrine and cyclopentyladenosine resulted in a synergistic increase in phosphoinositide hydrolysis either in the absence or in the presence of external calcium. In the presence of external calcium and a calcium ionophore, and adenosine agonist caused a significant stimulation of phosphoinositide hydrolysis without the addition of norepinephrine. Influx of extracellular calcium through voltage-sensitive calcium channels did not appear to be required to observe an effect of cyclopentyladenosine, because neither calcium channel antagonists (nifedipine, verapamil, and LaCl3) nor a chelator of extracellular calcium (ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid) were able to alter the degree of potentiation of norepinephrine-stimulated phosphoinositide hydrolysis due to the adenosine agonist. On the other hand, buffering of intracellular calcium concentration with the membrane-permeant calcium chelator quin2 blocked the potentiation. This blockade of potentiation by quin2 was reversed by the addition of extracellular calcium. Agents that stimulated cAMP production or membrane-permeable analogues of cAMP also blocked the action of the adenosine agonist to potentiate norepinephrine-stimulated phosphoinositide hydrolysis. This effect of cAMP was less pronounced in the presence of elevated extracellular calcium and was abolished in the presence of a calcium ionophore. When norepinephrine-stimulated calcium transients were quantitated using fura-2 fluorescence, a reduction in the amplitude of the calcium response was observed in the presence of forskolin. Conversely, both the amplitude and the duration of the calcium response were enhanced by the addition of the adenosine agonist. The results of these studies suggest that the mechanism by which adenosine receptors enhance the stimulation of phosphoinositide hydrolysis is dependent upon a rise in intracellular Ca2+ concentration resulting from the simultaneous activation of alpha 1-adrenergic receptors. The results further suggest that cAMP inhibits this mechanism by decreasing the norepinephrine-stimulated rise in intracellular Ca2+ concentration.
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PMID:Competitive regulation of phospholipase C responses by cAMP and calcium. 131 17

Induction of polyphosphoinositide hydrolysis in cardiac tissue by IgG from chagasic mice was assayed. BALB/c mice auricles were labelled with myo-[3H]inositol precursor and inositol phosphate production in the presence or absence of chagasic IgG and the corresponding F(ab')2 was measured. Both chagasic IgG and F(ab')2 but not the normal forms specifically increased phosphoinositide turnover. This increment was blocked by muscarinic cholinergic antagonists and to an even greater extent by the phospholipase C inhibitor NCDC. Moreover, calcium channel blocking agents such as diltiazem, verapamil and D-600 also exerted an inhibitory action. A muscarinic cholinergic agonist, carbachol, and the ionophore A-23187, mimicked the action of the chagasic IgG upon phosphoinositide turnover. It is concluded that murine chagasic IgG and its F(ab')2 fragments result in stimulation of phospholipase C-mediated phosphoinositide hydrolysis through the interaction with muscarinic cholinergic receptors requiring the cytosolic calcium concentration to be raised.
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PMID:Chagasic IgG stimulates phosphoinositide hydrolysis via neurotransmitter receptor activation: role of calcium. 133 20

We have investigated the effect of cholecystokinin-octapeptide (CCK-8) on [Ca2+]i and protein kinase C (PKC) activity in Jurkat T-cells. CCK-8 produced a transient [Ca2+]i increase in the presence of extracellular Ca2+. While CCKB receptor antagonist L-365,260 abolished the elevation of [Ca2+]i, CCKA receptor antagonist L-364,718 was without effect. Moreover, the dihydropyridine calcium channel blocker nitrendipine was shown to block the observed calcium response. Results suggest that the calcium effect is caused by an interaction of CCK-8 with CCKB binding sites and an influx of external Ca2+ via dihydropyridine sensitive calcium channels might serve as a source for the increased [Ca2+]i. Because CCK-8 induced no PKC activation CCKB receptor mediated rise of intracellular calcium seems not to include activation of phospholipase C.
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PMID:CCKB receptor stimulation mediates [Ca2+]i increase but no PKC activation in Jurkat T-cells. 152 Aug 57

We have previously shown that alpha-thrombin exerted a mitogenic effect on human glomerular epithelial cells and stimulated the synthesis of urokinase-type (u-PA) and tissue-type plasminogen activator (t-PA) and of their inhibitor, plasminogen activator inhibitor 1 (PAI-1). In the present study, we investigate the signal transduction mechanisms of thrombin in these cultured cells. Thrombin induced an increase in intracellular free calcium concentrations ([Ca2+]i) in a dose-dependent manner, a plateau being reached at 1 U/ml thrombin. A 60% inhibition of this effect was produced by 300 nM nicardipine, a dihydroperidine agent, or by 4 mM EGTA, indicating that increase in [Ca2+]i was due in part to extracellular Ca2+ entry through L-type voltage-sensitive calcium channels. Thrombin also induced an increase in inositol trisphosphate (IP3), suggesting that phospholipase C activation and phosphatidylinositides breakdown were stimulated. Interestingly thrombin-stimulated cell proliferation measured by 3H thymidine incorporation was inhibited by 300 nM nicardipine, and restored by addition of 10(-8) M ionomycin, indicating that calcium entry was critical for the mitogenic signal of thrombin. Conversely, nicardipine did not modify thrombin-stimulated synthesis of u-PA, t-PA, and PAI-1. Both thrombin-stimulated cell proliferation and protein synthesis required protein kinase C activation since these effects were blocked by 10 microM H7, an inhibitor of protein kinases, and by desensitization of protein kinase C by phorbol ester pretreatment of the cells. Interestingly, DFP-inactivated thrombin which binds the thrombin receptor and gamma-thrombin, which has some enzymatic activity but does not bind to thrombin receptor, had no effect when used alone. Simultaneous addition of these two thrombin derivatives had no effect on [Ca2+]i, and 3H thymidine incorporation but stimulated u-PA, t-PA, and PAI-1 synthesis although to a lesser extent than alpha-thrombin. This effect also required protein kinase C activation to occur, presumably by a pathway distinct from phosphoinositoside turnover since it was not associated with IP3 generation. In conclusion, multiple signalling pathways can be activated by alpha-thrombin in glomerular epithelial cells: 1) Ca2+ influx through a dihydroperidine-sensitive calcium channel, which seems critical for mitogenesis; 2) protein kinase C activation by phosphoinositide breakdown, which stimulates both mitogenesis and synthesis of u-PA, t-PA, and PAI-1; 3) protein kinase C activation by other phospholipid breakdown can stimulate u-PA, t-PA, and PAI-1 synthesis but not mitogenesis.
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PMID:Thrombin signal transduction mechanisms in human glomerular epithelial cells. 153 79

The activation of phospholipase D by platelet-activating factor (PAF) in the human promonocytic cell line U937 has been investigated. In cells prelabeled with [3H]palmitic acid, addition of PAF or phorbol 12-myristate 13-acetate (PMA) induced the synthesis of [3H]phosphatidylethanol, indicating phospholipase D activation. When U937 cells were preincubated for 5 min with PMA, and then stimulated with PAF, formation of phosphatidylethanol was greatly enhanced. In contrast, under the same experimental conditions PMA treatment blocked completely the PAF-induced inositol phosphates formation in cells prelabeled with [3H]inositol. Thus, PMA treatment demonstrates that phospholipase D activation can occur independently from phosphoinositide-specific phospholipase C activation during PAF stimulation in U937 cells. On the other hand, the data herein presented suggest that influx of external calcium is required for phospholipase D activation by PAF, as assessed by complete inhibition of the enzyme activity by chelation of extracellular calcium or by treatment with the calcium channel blocker verapamil. Based on these findings, a hypothetical model for phospholipase D activation is discussed.
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PMID:Platelet-activating factor synergizes with phorbol myristate acetate in activating phospholipase D in the human promonocytic cell line U937. Evidence for different mechanisms of activation. 165 58

The pressor actions of arginine vasopressin (AVP) were examined in pithed Sprague-Dawley and Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Prior to pithing, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded via an intra-arterial catheter from sodium pentobarbital anaesthetized rats. SBP and DBP recorded from SHR were significantly greater than those from Sprague-Dawley and WKY rats. However, after pithing, there were no significant differences between DBP among the various strains. Pertussis toxin pretreatment significantly reduced the prepithing SBP and DBP of the SHR but not Sprague-Dawley or WKY rats. Administration of nifedipine significantly reduced DBP of pithed rats. The dose-diastolic pressure response curves obtained from infusion of AVP in Sprague-Dawley and WKY rats were not significantly different from one another, but the maximal vasopressor responses to AVP in pithed SHR were enhanced. Administration of nifedipine to Sprague-Dawley and WKY rats did not affect the dose-response curve to AVP, but nifedipine administration in SHR led to a significant inhibition of the pressor responses to AVP. Furthermore, pertussis toxin pretreatment of rats significantly reduced a component of the AVP pressor effect in SHR but not Sprague-Dawley or WKY rats. We speculate that, in SHR, vasopressin receptors are coupled to a pertussis toxin-sensitive G protein that, in turn, may couple to a dihydropyridine-sensitive calcium channel and also to a pertussis-insensitive G protein that is probably coupled to the phospholipase C/intracellular calcium release process. A component of the elevated blood pressure in SHR is also regulated by a pertussis toxin-sensitive process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pressor actions of arginine vasopressin in pithed Sprague-Dawley, Wistar-Kyoto and spontaneously hypertensive rats before and after treatment with nifedipine or pertussis toxin. 166 82

The role of pertussis toxin-sensitive guanine nucleotide regulatory proteins (G-proteins) in the signal transduction process(es) involved in postjunctional vascular alpha 1-adrenoceptor-mediated vasoconstriction produced by the full agonist, cirazoline, and the partial agonist, (-)-dobutamine, have been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 micrograms/kg, iv, 3 days prior to experimentation) only slightly inhibited the pressor response of cirazoline, and the degree of inhibition produced by pertussis toxin was roughly equivalent to the inhibition produced by the calcium channel antagonist, nifedipine (1 mg/kg, ia). In contrast, pertussis toxin pretreatment produced marked inhibition of the alpha 1-adrenoceptor-mediated pressor response to the partial agonist, (-)-dobutamine, and this large degree of inhibition was qualitatively and quantitatively similar to the degree of inhibition produced by nifedipine. The differential pattern of inhibition of full and partial alpha 1-adrenoceptor agonists by pertussis toxin suggests that the vasoconstrictor response of an alpha 1-adrenoceptor partial agonist, which is more dependent upon the translocation of extracellular calcium than a full agonist, as evidenced by its sensitivity to inhibition by nifedipine, involves a pertussis toxin-sensitive G-protein that couples the alpha 1-adrenoceptor to the calcium channel. Furthermore, for alpha 1-adrenoceptor-mediated vasoconstriction by full agonists with high intrinsic efficacy, which involves both intracellular and extracellular pools of calcium, and particularly the former, pertussis toxin only inhibits that component of the alpha 1-adrenoceptor response which is dependent upon the translocation of extracellular calcium, accounting for the limited degree of inhibition of the response to cirazoline by pertussis toxin and by nifedipine. By inference, the other component of the alpha 1-adrenoceptor-mediated pressor response to a full agonist, which is dependent upon the mobilization of intracellular stores of calcium through a process believed to involve the activation of phospholipase C, likely utilizes a pertussis toxin insensitive G-protein that is distinct from that which we propose couples the alpha 1-adrenoceptor to the calcium channel. We conclude, therefore, that the alpha 1-adrenoceptor in the vasculature of the pithed rat may be coupled to 2 distinct G-proteins, only one of which is sensitive to inhibition by pertussis toxin and links the alpha 1-adrenoceptor to the membrane calcium channel, and which may be utilized by both full agonists and partial agonists.
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PMID:The effect of pertussis toxin on alpha 1-adrenoceptor-mediated vasoconstriction by the full agonist, cirazoline, and the partial agonist, (-)-dobutamine, in pithed rats. 167 94

In primary cultures of anterior pituitary cells, dopamine inhibited basal and thyrotropin-releasing hormone (TRH)-stimulated inositol monophosphate, bisphosphate, and trisphosphate production. This inhibition by dopamine can be resolved into two distinct components. One of the components was rapid and already present after 10 s. The other was slower, starting after 1 min, and was mimicked by nimodipine, a dihydropyridine calcium channel antagonist. The effects of dopamine and nimodipine were not additive on both basal and TRH-stimulated inositol phosphate production. Furthermore, the dopamine inhibition in the presence of TRH was much higher than the inhibition induced by nimodipine. It is thus likely that calcium entry through voltage-dependent calcium channels triggers a positive feedback on TRH stimulation of phospholipase C. However, depolarizing concentrations of K+ or BAY-K-8644, a voltage-dependent calcium channel agonist, had no effect on inositol monophosphate and bisphosphate accumulation. Ionomycin, even at a very high concentration (10 microM), had only a slight and transient effect on inositol phosphate formation. In addition, these agents did not affect the TRH dose-dependent stimulation of inositol phosphate production. These results suggest that the intracellular calcium concentrations that we measured under basal and TRH-stimulated conditions are sufficient to allow the maximal activity of phospholipase C which can be obtained under these two experimental conditions. In contrast, any decrease in the intracellular calcium concentration by a dihydropyridine antagonist, suppression of extracellular calcium, or inactivation of a voltage-dependent calcium channel by long term depolarization with K+ decreased the phospholipase C activities measured under basal and TRH-stimulated conditions. From these data it can be concluded that dopamine inhibits inositol phosphate production by two distinct mechanisms. The slow dopamine-induced inhibition of TRH-stimulated inositol phosphate production which is mimicked by nimodipine is likely because of an inhibition of a voltage-dependent calcium channel. This is substantiated further by the fact that ionomycin (10 microM) was able to reverse the nimodipine inhibitions as well as this slow component of dopamine inhibition. The nature of the rapid inhibition of TRH-stimulated inositol phosphate production induced by dopamine, but not by nimodipine, remains to be determined. It is suppressed in the absence of extracellular Ca2+. This may suggest that this inhibition is related to blockade of non-dihydropyridine-sensitive Ca2+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dual mechanisms of inhibition by dopamine of basal and thyrotropin-releasing hormone-stimulated inositol phosphate production in anterior pituitary cells. Evidence for an inhibition not mediated by voltage-dependent Ca2+ channels. 169 37

The 29-amino-acid peptide galanin (GAL) caused concentration-dependent inhibition of the accumulation of 3H-inositol phosphates (3H-InsPs) induced by the muscarinic agonist carbachol (CARB; 10(-3)-10(-5) M) in the presence of 5 mM lithium, specifically in tissue miniprisms from rat ventral hippocampus. The inhibitory effect of GAL involved the mono-, bis-, tris-, and tetrakisphosphates formed during activation for 2 min of phospholipase C by CARB (1 mM) in the absence of lithium. GAL (1 microM) did not affect alpha-adrenergic or serotonergic type 2 receptor-mediated phosphoinositide (PI) breakdown in the same tissue. GAL by itself neither acted on basal levels of 3H-InsPs nor affected muscarinic receptors in binding studies. Blockade of the T-, N-, and L-types of voltage-sensitive calcium channel (VSCC) with 200 microM Cd2+ reduced muscarinic receptor-mediated PI breakdown by 50% and abolished the inhibitory effect of GAL (1 microM). Reduction of the extracellular Ca2+ concentration from 1.3 mM to 0.49 microM abolished the GAL inhibition of CARB-stimulated PI hydrolysis. Ca2+ influx promoted by 18 mM K+ depolarization or by 1 microM Bay K 8644, a selective agonist of the L-type VSCC, prevented the inhibitory effect of GAL. Blockade of the L-type VSCC with nifedipine (1 microM) potentiated the inhibitory effects of GAL without affecting muscarinic stimulation of PI breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Galanin reduces carbachol stimulation of phosphoinositide turnover in rat ventral hippocampus by lowering Ca2+ influx through voltage-sensitive Ca2+ channels. 170 18


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