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 the present study, we investigated the effect of high density lipoproteins 3 (HDL3) on Na+/H+ exchanger activity and cytosolic pH (pHi) in human platelets. HDL3 alone failed to affect pHi, but preincubation with HDL3 significantly enhanced the Na+/H+ antiport activation brought about by acidification with 100 mM sodium propionate or stimulation with 0.05 U/ml thrombin. the stimulatory effect of HDL3 was unaffected by indomethacin excluding a role for cyclooxygenase products. The HDL3 effect was not mediated by Ca2+/calmodulin-dependent protein kinase as HDL3 failed to increase cytosolic free calcium concentration. However, the potentiating effect of HDL3 was completely blocked in the presence of the protein kinase C inhibitor, bisindoylmaleimide and the phosphatidylcholine-specific phospholipase C inhibitor, D609. Furthermore, the effect of HDL3 was abolished after covalent modification of HDL3 with dimethylsuberimidate and was not observed in platelets from Glanzmann thrombasthenia type 1 which do not express GP IIb/IIIa, as well as in platelets preincubated with anti-GP IIb/IIIa polyclonal antibodies. We conclude that HDL3 enhances the sodium propionate- and thrombin-induced Na+/H+ antiport activity in human platelets via binding to GP IIb/IIIa and activation of protein kinase C and phosphatidylcholine-specific phospholipase C.
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PMID:High density lipoproteins enhance the Na+/H+ antiport in human platelets. 874 92

The Na+/Ca2+ exchanger plays an important role in the maintenance of calcium homeostasis in the heart. Therefore, factors which regulate the exchanger have a significant impact on cardiac function. Previously, we showed that the non-hydrolysable GTP analog, 5'guanylyl imidodiphosphate [Gpp(NH)p], stimulates Na+/Ca2+ exchange activity, implying the involvement of a G protein in exchanger regulation. In this study, we examined the effect of G protein agonists on Na+/Ca2+ exchanger activity. Isoproterenol, a Gs agonist, had no effect on exchanger activity. Likewise, the Gi agonist, carbachol, did not influence Na+/Ca2+ exchanger activity. Since these G proteins couple to the adenylate cyclase system, it would appear that cAMP-linked events do not regulate the Na+/Ca2+ exchanger. We next examined the influence of Gq-linked agonists on exchanger activity. Phenylephrine, an alpha 1-adrenergic agonist, increased Na+/Ca2+ exchanger activity up to 111% with an EC50 of 21 microM. Moreover, the Na+/Ca2+ exchanger activity was enhanced by angiotensin II and endothelin 1, which caused maximal stimulation of exchanger activity up to 125% and 211%, respectively. The selective protein kinase C inhibitor chelerythrine significantly attenuated the ability of phenylephrine and angiotensin II to stimulate the Na+/Ca2+ exchanger. In addition, the protein kinase C activator, phorbol 12-myristate 13-acetate, stimulated exchanger activity by 32%, raising the possibility that all three Gq agonists mediate their actions in part through the promotion of phospholipase C activity and the subsequent activation of protein kinase C. The contribution of Na+/Ca2+ exchange to the actions of phenylephrine, angiotensin II, and endothelin 1 is discussed.
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PMID:Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin 1. 874 10

Although phosphatidic acid (PA) is mainly formed due to the hydrolysis of phosphatidylcholine by myocardial phospholipase D, its functional significance in the heart is not fully understood. The present study was designed to determine the effects of PA on intracellular free Ca2+ level ([Ca2+]i) in freshly isolated adult rat cardiomyocytes by using fura 2-acextoxmethylester and free fura 2 technique. Addition of PA at concentrations of 1-200 microM produced a concentration-dependent increase in [Ca2+]i from the basal level of 117 +/- 8 nM; maximal increase in [Ca2+]i was 233 +/- 50 nM, whereas median effective concentration (EC50) for PA was 45 +/- 1.2 microM. This increase in [Ca2+]i was abolished by the removal of extracellular Ca2+ with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and was partially attenuated by Ca2+ channel blockers, verapamil or diltiazem. Preincubation of cardiomyocytes with cyclopiazonic acid and thapsigargin or with ryanodine [to deplete sarcoplasmic reticulum (SR) Ca2+] attenuated the PA-induced increase in [Ca2+]i by 66, 37, and 43%, respectively. Furthermore, the response of [Ca2+]i to PA was blunted by 2-nitro-4 carboxyphenylcarbonate, an inhibitor of phospholipase C, but was unaffected by staurosporine, a protein kinase C inhibitor. PA was also observed to induce Ca2+ efflux from the myocytes. In addition, an injection of PA (0.34 microgram/100 g body wt i.v.) in rats produced a significant increase of the left ventricular developed pressure as well as the maximum rates of cardiac contraction and relaxation within 5 min. These data suggest that the PA-induced increase in [Ca2+]i in cardiomyocytes is a consequence of both Ca2+ influx from the extracellular source and Ca2+ release from the intracellular SR stores. Furthermore, these in vitro data suggest the possibility that PA may regulate [Ca2+]i and contractile parameters in the heart.
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PMID:Phosphatidic acid increases intracellular free Ca2+ and cardiac contractile force. 877 Jan 8

ATP activated the K+ channel responsible for outwardly rectifying currents via a P2Y purinoceptor linked to a pertussis toxin-insensitive G-protein in cultured rat spinal neurons. The evoked currents were inhibited by a selective protein kinase C inhibitor, GF109203X, whereas a phospholipase C inhibitor, neomycin had no effect. These indicate that the currents are regulated by phospholipase C-independent protein kinase C activation. In addition, ATP enhanced intracellular free Ca2+ concentration. The increase in intracellular free Ca2+ concentration was inhibited by a broad G-protein inhibitor, GDP beta S, but not affected by neomycin or an inositol 1,4,5-triphosphate receptor antagonist, heparin, suggesting that the cytosolic Ca2+ mobilization is regulated by a mechanism independent of a phospholipase C-mediated phosphatidylinositol signaling. These results, thus, demonstrate that ATP has dual actions on the coupled K+ channel and cytosolic Ca2+ release.
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PMID:ATP-regulated K+ channel and cytosolic Ca2+ mobilization in cultured rat spinal neurons. 879 Oct 4

Bradykinin is a mediator of the protection of myocardium by angiotensin I-converting enzyme/kininase II inhibitors. We reported that the activation of B2 bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP3). Here we examine the regulation of IP3 formation stimulated by bradykinin. Activation of myocytes with 1 mu/L bradykinin increased IP3 production from 117 +/- 8.3 to 1011 +/- 48.6 pmol/mg protein. Treatment of the cells with 10 mu/L indomethacin or 1 mu/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (p-amylcinnamoyl) anthranilic acid, a phospholipase A2 inhibitor, blunted the IP3 response to bradykinin. Because thromboxane A2 stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A2 receptor antagonist BM 13177 (1 mu/L), which strongly attenuated the stimulated IP3 production. Since thromboxane A2 appears to partly mediate the IP3 response to bradykinin, we examined the effect of the stable thromboxane A2 mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629 +/- 14.5 versus 1011 +/- 48.6 pmol IP3/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A2 blunted the IP3 response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 mu/L) attenuated the IP3 accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 mu/L staurosporine, a protein kinase C inhibitor. Treatment with 1 microgram/mL cholera toxin or pertussis toxin for 4 hours amplified the IP3 response to 10 nmol/L bradykinin from 570 +/- 20.0 to 1150 +/- 51.3 and to 1016.7 +/- 21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B2 bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 mu/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP3 production mostly via phospholipase A2 stimulation and thromboxane A2 formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP3 and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A2, is negatively regulated by protein kinase C activation.
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PMID:Thromboxane A2 mediates the stimulation of inositol 1,4,5-trisphosphate production and intracellular calcium mobilization by bradykinin in neonatal rat ventricular cardiomyocytes. 879 31

Vasoactive peptides mobilize cytosolic free Mg2+ in vascular smooth muscle cells. It is unknown whether angiotensin II and arginine vasopressin, potent vasoconstrictor agents, influence intracellular Mg2+. The effects of angiotensin II and vasopressin on intracellular free Mg2+ concentrations ([Mg2+]i) were therefore investigated in primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric arteries of Wistar Kyoto rats, and in an established cell line of rat thoracic aorta cells (A10 cells). Underlying mechanisms of agonist-stimulated [Mg2+]i changes were assessed in A10 cells by pharmacologically manipulating phospholipase C, protein kinase C, and the Na+/H+ exchanger. In addition, the dependence of [Mg2+]i on intracellular Ca2+ was determined. [Mg2+]i was measured in single cells by fluorescent digital imaging using mag-fura-2/AM. Basal [Mg2+]i levels in Wistar Kyoto rat and A10 cells were 0.62 +/- 0.02 mmol/liter and 0.58 +/- 0.01 mmol/liter, respectively. Angiotensin II and vasopressin induced a dose-dependent biphasic [Mg2+]i response where [Mg2+]i increased rapidly and transiently to a peak level and then declined to subbasal levels, which were sustained. Preexposure of cells to neomycin, a nonspecific phospholipase C inhibitor, U-73122, a selective phospholipase C inhibitor, calphostin C, a selective protein kinase C inhibitor, and 5-(N, N-hexamethylene)amiloride, a selective Na+/H+ exchange blocker, attenuated angiotensin II- and vasopressin-induced [Mg2+]i responses in a concentration-dependent manner. Removal of extracellular Na+ completely inhibited agonist-elicited [Mg2+]i transients. To determine whether intracellular free Ca2+ concentration ([Ca2+]i) influences agonist-induced [Mg2+]i changes, thapsigargin, a selective sarcoplasmic reticular Ca2+-ATPase inhibitor, was used to deplete intracellular Ca2+ stores. In thapsigargin-pretreated cells, angiotensin II-elicited [Ca2+]i responses were significantly attenuated, whereas agonist-induced [Mg2+]i responses were unchanged. These data demonstrate that in primary cultured VSMC and in an established VSMC line, angiotensin II and vasopressin modulate [Mg2+]i through receptor-mediated pathways, which are [Ca2+]i-independent but which involve phospholipase C, protein kinase C, and the Na+/H+ exchanger. These pathways are linked to a Na+-dependent Mg2+ transporter, which facilitates transmembrane Mg2+ transport.
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PMID:Angiotensin II and vasopressin modulate intracellular free magnesium in vascular smooth muscle cells through Na+-dependent protein kinase C pathways. 879 89

1. Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD-coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined. 2. The mGluR-selective agonist (1S,3R)-l-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] induced a concentration-dependent (10-300 microM) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments. 3. The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine > (1S,3R)-ACPD > L-cysteine sulphinic acid > L-aspartate > L-glutamate. L-(+)-2-Amino-4-phosphonobutyric acid and the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate failed to activate PLD. (RS)-3,5-dihydroxyphenylglycine (100300 microM), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 microM (1S,3R)-ACPD. 4. (+)-alpha-Methyl-4-carboxyphenylglycine (0.1-1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L-(+)-2-Amino-3-phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 microM (1S,3R)-ACPD-induced PLC response but produced a robust stimulation of PLD. 5. 12-O-Tetradecanoylphorbol 13-acetic acid and phorbol 12,13-dibutyrate (PDBu), activators of protein kinase C, at 1 microM had a stimulatory effect on mGluRs linked to PLD but depressed (1S,3R)-ACPD-induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 microM) reduced PLD activation induced by 1 microM PDBu but not by 100 microM (1S,3R)-ACPD. 6. Our results suggest that PLD-linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC-independent mechanism.
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PMID:Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus. 879 79

The effects of adenosine on hippocampal neurons were examined by patch-clamp recording and Ca2+ imaging using fura-2 fluorescence. In the whole-cell patch-clamp configuration, adenosine evoked outwardly rectifying K+ currents in a dose-dependent manner. These currents were not inhibited by a nonselective P1 purinoceptor antagonist or selective adenosine A1, A2A receptor antagonists and moreover, selective adenosine A1, A2A receptor agonists evoked no current. In contrast, P2 purinoceptor agonists produced similar outward currents with the order of potency: ADP > or = 2-methylthio ATP > ATP > adenosine >> AMP. No response was obtained to UTP, alpha, beta-methylene ATP or beta, gamma-methylene ATP. The intracellular perfusion of a broad G-protein inactivator, guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), abolished adenosine-evoked currents, whereas a Gi/Go-protein inhibitor, pertussis toxin, had no effect. Furthermore, the currents were blocked by a phospholipase C inhibitor, neomycin, or specific protein kinase C inhibitors, GF109203X (bisindolyl maleimide, C25H24N4O2) and protein kinase C inhibitor peptide. In the cell-attached patch-clamp configuration, adenosine elicited single-channel currents with two major kinds of slope conductances. Likewise, application of adenosine outside the patch electrode again produced single-channel currents with same conductances. A potent protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), induced single-channel currents in a fashion that mimics the effect of adenosine. The evoked currents were blocked by GF109203X. In addition, adenosine enhanced intracellular free Ca2+ concentration ([Ca2+]i). This [Ca2+]i increase was inhibited by GDP beta S or neomycin, but was not affected by pertussis toxin. These results, thus, suggest that adenosine activates the K+ channel and enhances cytosolic Ca2+ release via a P2Y purinoceptor linked to a pertussis toxin-insensitive G-protein, which is involved in a phospholipase C-mediated phospholipid-signaling pathway.
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PMID:Adenosine activates the K+ channel and enhances cytosolic Ca2+ release via a P2Y purinoceptor in hippocampal neurons. 881 2

The mRNA coding for H-ferritin was highly induced in human monocytic THP-1 cells following treatment with phorbol 12-myristate 13-acetate (PMA). The induction was detected at 3 h, reached maximal levels at 12 h, and was sustained for up to 48 h subsequent to PMA exposure. PMA-induced up-regulation of H-ferritin gene expression was also observed in other leukaemic cell lines, HL60 and U937, but not in non-leukaemic cell types, including human fibroblasts, endothelial cells and smooth muscle cells. The effect of PMA could be completely blocked by the protein kinase C inhibitor, H-7. Furthermore, treatment of THP-1 cells with bacterial phospholipase C also produced a marked increase in expression of H-ferritin mRNA, suggesting the activation of protein kinase C was responsible for the accumulation of mRNA. Nuclear run-off experiments demonstrated that PMA did not increase the transcriptional rate of the H-ferritin gene. In contrast, the half-life of the H-ferritin mRNA measured in the presence of actinomycin D was greatly prolonged in PMA-treated cells. The induction of H-ferritin mRNA by PMA required no protein synthesis. Conversely, treatment of THP-J cells with protein synthesis inhibitor, cycloheximide, resulted in a 4-5-fold increase in H-ferritin mRNA. The increase in the stability of the H-ferritin mRNA was also observed in cells treated with cycloheximide. Taken together, these results suggest that the stability of H-ferritin mRNA in THP-1 is subjected to regulation via a protein kinase C-mediated phosphorylation on existing putative protein factor(s).
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PMID:Post-transcriptional regulation of H-ferritin gene expression in human monocytic THP-1 cells by protein kinase C. 887 Jun 67

1. Pharmacological characterization of different lysophosphatidylcholines was performed based on their effect on the Ca2+ sensitivity of contraction in alpha-toxin-permeabilized rat mesenteric arteries. Furthermore, the effect of noradrenaline on [3H]-myristate-labelled lysophosphatidylcholine levels was assessed, to investigate whether lysophosphatidylcholines could be second messengers. 2. Palmitoyl or myristoyl L-alpha-lysophosphatidylcholine increased the sensitivity to Ca2+, whereas lysophosphatidylcholines containing other fatty acids had less or no effect. 3. L-alpha-phosphatidylcholine, L-alpha-glycerophosphorylcholine, palmitic acid, myristic acid and choline, potential metabolites of lysophosphatidylcholines, did not affect contractions. 4. Noradrenaline (GTP was required) and GTP gamma S increased the sensitivity to Ca2+, and GDP-beta-S inhibited the effect of noradrenaline. Lysophosphatidylcholines, however, had no requirement for GTP and caused sensitization in the presence of GDP-beta-S. 5. Calphostin C, a relatively specific protein kinase C inhibitor, did not affect contraction induced by Ca2+, but abolished the sensitizing effect of lysophosphatidylcholine. 6. Noradrenaline caused no measurable changes in the levels of [3H]-myristate-labelled phosphatidylcholine and lysophosphatidylcholine at 30 s and 5 min stimulation. 7. These results suggest that lysophosphatidylcholines can increase Ca2+ sensitivity through a G-protein-independent, but a protein kinase C-dependent mechanism. However, the role for lysophosphatidylcholines as messengers causing Ca2+ sensitization during stimulation with noradrenaline remains uncertain because no increase in [3H]-myristate labelled lysophosphatidylcholine could be measured during noradrenaline stimulation.
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PMID:Increase by lysophosphatidylcholines of smooth muscle Ca2+ sensitivity in alpha-toxin-permeabilized small mesenteric artery from the rat. 888 21


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