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)

We investigated the effects of 17beta-estradiol, an estrogen, on [(3)H]norepinephrine ([(3)H]NE) secretion in PC12 cells. Pretreatment with 17beta-estradiol reduced 70 mM K(+)-induced [(3)H]NE secretion in a concentration-dependent manner with a half-maximal inhibitory concentration (IC(50)) of 2 +/- 1 microM. The 70 mM K(+)-induced cytosolic free Ca(2+) concentration ([Ca(2+)](i)) rise was also reduced when the cells were treated with 17beta-estradiol (IC(50) = 15 +/- 2 microM). Studies with voltage-sensitive calcium channel (VSCC) antagonists such as nifedipine and omega-conotoxin GVIA revealed that both L- and N-type VSCCs were affected by 17beta-estradiol treatment. The 17beta-estradiol effect was not changed by pretreatment of the cells with actinomycin D and cycloheximide for 5 h. In addition, treatment with pertussis or cholera toxin did not affect the inhibitory effect of 17beta-estradiol. 17beta-Estradiol also inhibited the ATP-induced [(3)H]NE secretion and [Ca(2+)](i) rise. In PC12 cells, the ATP-induced [Ca(2+)](i) rise is known to occur through P2X(2) receptors, the P2Y(2)-mediated phospholipase C (PLC) pathway, and VSCCs. 17beta-Estradiol pretreatment during complete inhibition of the PLC pathway and VSCCs inhibited the ATP-induced [Ca(2+)](i) rise. Our results suggest that 17beta-estradiol inhibits catecholamine secretion by inhibiting L- and N-type Ca(2+) channels and P2X(2) receptors in a nongenomic manner.
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PMID:Nongenomic inhibition of catecholamine secretion by 17beta-estradiol in PC12 cells. 1082 Feb 10

This study was conducted to examine the mechanism(s) of synergistic interaction of histamine- and adrenaline-mediated human platelet aggregation. We found that platelet aggregation mediated by subthreshold concentrations of histamine (1-4 microm) plus adrenaline (0.5-2 microm) is inhibited by both an alpha(2)-adrenoceptor blocker (yohimbine) and a histamine (H1) receptor antagonist (diphenhydramine). In examining the role of the downstream signalling pathway, we found that such an interaction is inhibited by the calcium channel blockers verapamil and diltiazem. However, platelet aggregation by adrenaline plus histamine was inhibited by very low concentrations of the phospholipase C (PLC) inhibitor, U73122 (IC(50)= 1.2 microm), the MEK inhibitor, PD98059 (IC(50)= 1.1 microm) and the cyclo-oxygenase (COX) inhibitor, indomethacin (IC(50)= 7 microm). However the inhibition of receptor tyrosine kinase, protein kinase C and phosphatidylinositol 3-kinase by genistien, chelerythrine and wortmannin, respectively, had no significant effect on aggregation. Similarly the nitric oxide donor (SNAP) had no effect on this synergism. These data suggest that the synergistic effect of histamine and adrenaline during human platelet aggregation is receptor mediated and involves activation of PLC, COX and MAP kinase signalling pathways.
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PMID:Synergistic interaction of adrenaline and histamine in human platelet aggregation is mediated through activation of phospholipase, map kinase and cyclo-oxygenase pathways. 1102 12

Osteoclasts "sense" elevated extracellular calcium, which leads to cytoskeletal changes that may be linked to phospholipase C (PLC) activation and the associated rise in intracellular calcium ([Ca(2+)](i)). Since PLC is linked to transient receptor potential channels (trp), we hypothesized that receptor activated calcium influx due to this channel type would be activated by osteoclasts sensing [Ca(2+)](e). We found that high [Ca(2+)](e) induced similar intracellular Ca(2+) rises in chicken osteoclasts with or without intracellular Ca(2+) store depletion by either TPEN or thapsigargin, thus defining store-insensitive Ca(2+) influx. This store-insensitive calcium sensing component was blocked by the PLC antagonist U73122. Also, the calcium channel inhibitor SKF 96365, a blocker of store-independent trp-like channels, was effective in inhibiting calcium sensing in the presence of thapsigargin. Thus, a store-independent component of calcium sensing was associated with ion channels linked to PLC. Since receptor activated transient receptor potential (trp) family cation channels open in a PLC-dependent and store-independent manner, we suggest that receptor operated channels are activated in osteoclasts stimulated by high extracellular Ca(2+).
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PMID:Receptor-operated osteoclast calcium sensing. 1131 62

Since volatile anesthetics inhibited high voltage-gated calcium channels and G-protein-coupled M(1) muscarinic signaling, their effects upon M(1) receptor-induced modulation of L-type (alpha1C) calcium channel was investigated. Voltage-clamped Ba(2+) currents (I(Ba)) were measured in Xenopus oocytes coexpressed with L-type channels and M(1) muscarinic receptors. M(1) receptor agonist, acetyl-beta-methylcholine (MCh) inhibited the peak and late components of I(Ba) in a dose-dependent manner. Analysis of I(Ba) after the treatment with MCh or volatile anesthetics revealed that the inactivating component, its time constant, and the noninactivating current were all decreased by these agents. MCh-induced inhibition followed a second messenger pathway that included G-proteins, phospholipase C, inositol-1,4,5-trisphosphate, and intracellular calcium [Ca(2+)](i). Although halothane or isoflurane inhibited I(Ba,) their effect was not mediated through these intracellular second messengers. By using volatile anesthetics and MCh sequentially, and in various combinations, the susceptibility of L-type currents and their modulation by M(1) receptors to volatile anesthetics were investigated. When MCh and volatile anesthetics were administered together simultaneously, a pronounced inhibition that was approximately equal to the sum of their individual effects was seen. Halothane or isoflurane further inhibited the I(Ba) when either volatile anesthetic was administered following the inhibition produced by prior administration of MCh. However, when MCh was administered following either volatile anesthetic, its effect was significantly reduced. Thus, whereas volatile anesthetics appear to directly inhibit L-type channels, they also interfere with channel modulation by G-protein-coupled receptors, which may have functional implications for both neuronal and cardiovascular tissues.
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PMID:Differential sensitivity of expressed L-type calcium channels and muscarinic M(1) receptors to volatile anesthetics in Xenopus oocytes. 1135 20

Parathyroid hormone (PTH) activates both adenylyl cyclase and phospholipase C via the PTH-1 receptor. We previously reported that PTH increased heart rate and that this effect was mediated via the pacemaker current (I f ). However, it has been reported that PTH exerts its chronotropic effect via an interaction with adrenergic receptors or via L-type calcium channels. Thus, the objective of the study was to elucidate the exact mechanism of the chronotropic effect of PTH. We tested whether its chronotropic effects could be abolished by inhibitors of the following systems in isolated perfused rat hearts: alpha-adrenergic (prazosin); beta-adrenergic (propranolol); angiotensin II (CV11974); endothelin-1 (TAK044); calcium channel (verapamil); adenylyl cyclase (miconazole); phospholipase C (U73122) or I f (CsCl). In addition, we measured the cyclic adenosine monophosphate level of the heart after PTH administration. Whereas prazosin, propranolol, CV11974, TAK044, verapamil, and U73122 did not inhibit the chronotropic effect of PTH, CsCl or miconazole suppressed it significantly. PTH increased the cyclic adenosine monophosphate level of the atrium but not the left ventricle. These results indicate that the chronotropic actions of PTH are mediated via selective activation of adenylyl cyclase to increase the I f current.
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PMID:Signaling pathway and chronotropic action of parathyroid hormone in isolated perfused rat heart. 1158 19

We compared agonist-evoked responses in the perfused mesenteric vascular bed (MVB) of streptozotocin (STZ) diabetic Sprague-Dawley rats 2 and 14 weeks after induction of diabetes. Endothelin-1 (ET-1)-, methoxamine (MTX)-, and KCl-evoked vasoconstrictor responses were unchanged in 2-week-old diabetic rats. In contrast, both the sensitivity (P < 0.01) and the maximal vasoconstrictor responses (P < 0.05) to ET-1 were attenuated in 14-week-old diabetic rats, whereas endothelin plasma levels were increased (P < 0.05). Although no differences were observed in responses to KCl in either the 2- or 14-week-old diabetic groups, MTX-evoked maximal responses were attenuated in the 14-week-old group (P < 0.01). Changes in agonist-evoked responses in the 14-week-old diabetic group were unaffected by the protein kinase C (PKC) inhibitor, staurosporine, the phospholipase C (PLC) inhibitor, U73122, the calcium channel blocker, nifedipine, the calcium pump inhibitor, cyclopiazonic acid (CPA), or by endothelial denudation. Sodium fluoride (NaF), an activator of guanosine triphosphate binding proteins (G proteins) normalized the responses in the 14-week-old diabetic group. These data suggest that advanced stages of STZ are associated with alterations in G protein receptor coupling and/or activity leading to the attenuation of responses to vasoconstrictor agonists.
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PMID:Attenuated agonist evoked vasoconstrictor responses in the perfused mesenteric vascular bed of streptozotocin diabetic rats. 1168 1

We investigated the combined effect of 5-hydroxytryptamine (5-HT, serotonin) and calcium ionophore (A23187) on human platelet aggregation. Aggregation, monitored at 37 degrees C using a Dual-channel Lumi-aggregometer, was recorded for 5 min after challenge by a change in light transmission as a function of time. 5-HT (2-200 microM) alone did not cause platelet aggregation, but markedly potentiated A23187 (low dose) induced aggregation. Inhibitory concentration (IC50) values for a number of compounds were calculated as means +/- SEM from dose-response determinations. Synergism between 5-HT (2-5 microM) and A23187 (0.5-2 microM) was inhibited by 5-HT receptor blockers, methysergide (IC50 = 18 microM) and cyproheptadine (IC50 = 20 microM), and calcium channel blockers (verapamil and diltiazem, IC50 = 20 microM and 40 microM respectively). Interpretation of the effects of these blockers is complicated by their lack of specificity. Similarly, U73122, an inhibitor of phospholipase C (PLC), blocked the synergistic effect at an IC50 value of 9.2 microM. Wortmannin, a phosphatidylinositide 3-kinase (PI 3-K) inhibitor, also blocked the response (IC50 = 2.6 microM). However, neither genistein, a tyrosine-specific protein kinase inhibitor, nor chelerythrine, a protein kinase C inhibitor, affected aggregation at concentrations up to 10 microM. We conclude that the synergistic interaction between 5-HT and ionophore may be mediated by activation of PLC/Ca2+ and PI 3-kinase signalling pathways, but definitive proof will require other enzyme inhibitors with greater specificity.
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PMID:Second messengers in platelet aggregation evoked by serotonin and A23187, a calcium ionophore. 1172 80

We have sought to elucidate the biochemical mechanisms that underlie the memory enhancing properties of the neural peptide vasopressin. Toward that goal we have investigated vasopressin induction of calcium signaling cascades, long held to be involved in long-term memory function, in neurons derived from the cerebral cortex, a brain region associated with long-term memory. Our previous studies demonstrated that in cultured cortical neurons, V1a vasopressin receptor (V1aR) activation resulted in a sustained rise in intracellular calcium concentration that was dependent on calcium influx (Son & Brinton, 1998). To investigate the mechanism of V1aR-induced calcium influx, we investigated V1aR activation of the calcium channel subtype(s) in cortical neurons cultured from Sprague-Dawley rat embryonic day 18 fetuses. The results of these analyses demonstrated that the L-type calcium channel blocker nifedipine blocked 250 nM V1 vasopressin receptor agonist (V1 agonist)-induced calcium influx. Intracellular calcium imaging analyses using fura-2AM demonstrated that blockade of L-type calcium channels prevented the 250 nM V1 agonist-induced rise in intracellular calcium concentration. These results indicate that the influx of extracellular calcium via L-type calcium channels is an essential step in the initiation of the V1 agonist-induced rise in intracellular calcium concentration. To determine the mechanism of V1aR activation of L-type calcium channels, regulatory components of the phosphatidylinositol signaling pathway were investigated. The results of these analyses demonstrated that V1 agonist-induced calcium influx was blocked by both a phospholipase C inhibitor (U-73122) and a protein kinase C inhibitor (bisindolylmaleimide I). Further analysis of V1aR activation of protein kinase C (PKC) demonstrated that V1 agonist induced PKC activity within 1 min of exposure in cultured cortical neurons. These data indicate that in cultured cortical neurons, V1aR activation regulates the influx of extracellular calcium via L-type calcium channel activation through a protein kinase-C-dependent mechanism. The results of these studies provide biochemical mechanisms by which vasopressin could enhance memory function. Those mechanisms include a complex cascade that is initiated by activation of the phosphatidylinositol pathway, activation of protein kinase C, followed by phosphorylation of L-type calcium channels to initiate the influx of extracellular calcium to activate a cascade of calcium-dependent release of intracellular calcium.
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PMID:Regulation and mechanism of L-type calcium channel activation via V1a vasopressin receptor activation in cultured cortical neurons. 1172 44

Calcium influx is required for the mammalian sperm acrosome reaction, an exocytotic event occurring in the sperm head after binding to the egg. Prior to this binding, the spermatozoon undergo, in the female reproductive tract, a series of biochemical transformations, collectively called capacitation. The first event in capacitation is the elevation of intracellular calcium, bicarbonate and hydrogen peroxide, which collectively activate adenylyl cyclase to produce cyclic-AMP, which activates protein kinase A. During capacitation, there is an increase in the membrane-bound phospholipase C, and this binding is highly stimulated by adding epidermal growth factor to the cells. We suggest that zona-pellucida binds to at least two different receptors in the sperm head plasma membrane. One is a G(i)-coupled receptor that can activate phospholipase Cbeta(1) and might regulate adenylyl cyclase to further enhance cyclic-AMP levels. The cyclic AMP activates protein kinase A to open a calcium channel in the outer acrosomal membrane, resulting in a relatively small rise in cytosolic calcium. This rise in Ca(2+) leads to activation of phospholipase Cgamma, which is coupled to the second tyrosine kinase receptor. The products of phospholipase C activity, diacylglycerol and inositol-trisphosphate (IP(3)), will lead to activation of protein kinase C (PKC) and IP(3)-receptor. PKC will open a calcium channel in the plasma membrane and IP(3) will activate the calcium channel in the outer acrosomal membrane, leading to a higher increase in cytosolic calcium. In addition, the depletion of calcium in the acrosome will activate a store-operated Ca(2+) channel, resulting in a very fast increase in cytosolic calcium (300-500 nM), leading to membrane fusion and completing the acrosome reaction.
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PMID:Role and regulation of intracellular calcium in acrosomal exocytosis. 1173 Sep 12

We have investigated the mechanisms regulating the expression of the mu-opioid receptor, using P19 mouse embryonal carcinoma cells, which normally lack this receptor, but which can be induced to express it in aggregated cells by retinoic acid treatment. The expression level of mu-opioid receptor mRNA was found to be closely correlated with aggregation status, and more specifically by cell to cell interaction requiring neural cell adhesion molecules (NCAM). We showed that NCAM activates the mu-opioid receptor gene through a pathway involving phospholipase C-arachidonic acid-calcium channel-calcium/calmodulin kinase II. A similar pathway was previously shown to promote neurite outgrowth, however, with distinct specificity, including the role of calcium channels. Activation of L-type calcium channels elevated mu-opioid receptor expression, while N-type-channel activity had the opposite effect. The effect of anti-NCAM-antibody treatment was not due to retardation of general neural development and was specific to the mu-opioid receptor gene. Our results indicate that the P19 system is an useful model to study the expression of the mu-opioid receptor gene.
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PMID:mu-Opioid receptor gene expression: the role of NCAM. 1173 27


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