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)

Q12713 substance, a cyclic peptide from Actinomadura spp., strongly inhibited the enzyme activity of phosphatidylinositol-4,5-bisphosphate-specific phospholipase C (PIP2-PLC) but scarcely inhibited other phospholipases. Kinetic analysis demonstrated that the inhibition of PIP2-PLC activity was competitive with respect to phosphatidylinositol 4,5-bisphosphate. Calcium and magnesium ions had no significant effect on the inhibitory activity. On the contrary, potassium or rubidium ion was essential for the inhibitory activity. Furthermore, NaF and AlCl3-stimulated increase of phosphoinositides was decreased by Q12713 in the cultured 3T3 cells.
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PMID:An inhibitor of inositol-phospholipid-specific phospholipase C. 838 82

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue 1-oleoyl-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats. 838 2

In pancreatic beta-cells, calcium is required for insulin secretion, but can also stimulate gene transcription. High potassium-induced membrane depolarization and calcium influx have previously been shown to activate kinases that phosphorylate and thereby activate the transcription factor cAMP response element (CRE-binding protein (CREB) binding to CREs. It is unknown, however, whether hormones and neurotransmitters can activate this mechanism. Arginine vasopressin (AVP), bombesin, and acetylcholine potentiate glucose-induced insulin secretion and are known to raise cytosolic calcium levels through binding to cell surface receptors that activate phospholipase C. The effect of AVP on CRE-directed transcription was examined in the beta-cell line HIT. AVP (0.1-100 nM) stimulated gene transcription after transient transfection of a reporter gene that was placed under the transcriptional control of a CRE. This effect was inhibited by a vasopressin V1 receptor antagonist and depended on calcium influx and calcineurin phosphatase activity. By immunoblots with antiphospho-CREB antibodies and by using a Gal4-CREB fusion protein, it was shown that AVP induces the phosphorylation and activation of CREB. Like AVP, bombesin (100 nM) and the muscarinic agonist carbachol (200 microM) stimulated CRE-mediated transcription. These results show that calcium-mediating insulin secretagogues can activate CREB/CRE-directed transcription in HIT cells, offering a mechanism by which these secretagogues could produce long term effects on beta-cell function, changing the pattern of gene expression.
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PMID:Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3',5'-monophosphate/calcium response element in a pancreatic islet beta-cell line. 853 17

Adenosine evoked whole-cell potassium currents and enhanced intracellular free Ca2+ concentration ([Ca2+]i) in superior colliculus neurons through a P2Y purinoceptor linked to a pertussis toxin-insensitive G-protein, possibly Gq-protein, which is involved in a protein kinase C (PKC) activation pathway. The [Ca2+]i increase was inhibited by a phospholipase C (PLC) inhibitor, whereas the evoked currents were not affected by a PLC inhibitor or a phospholipase A2 (PLA2) inhibitor. Adenosine elicited single channel currents via PKC activation in cell-attached patches and furthermore, those currents with conductances of the same slope were induced even in excised patches, suggesting that PKC can be activated only by cell membrane factors without intracellular components. These results thus indicate that the P2Y purinoceptor-coupled potassium channel is regulated via a novel PKC activation pathway independent of PLC or PLA2.
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PMID:Adenosine evokes potassium currents by protein kinase C activated via a novel signaling pathway in superior colliculus neurons. 854 92

A potent P2Y purinoceptor agonist, 2-methylthio ATP (2-MeSATP), produced whole-cell potassium currents through a purinoceptor linked to a pertussis toxin (PTX)-insensitive G-protein in rat hippocampal neurons. The currents were not affected by a selective protein kinase C or A inhibitor. Single channel recordings demonstrated that the potassium channel is activated without latency even in outside-out patches. These suggest that the channel may be regulated directly by the beta gamma subunits of a G-protein. In addition, 2-MeSATP enhanced intracellular free Ca2+ concentration ([Ca2+]i) with a very rapid initiation time. The [Ca2+]i increase was inhibited by a broad G-protein inhibitor, but not by a phospholipase C (PLC) inhibitor or an IP3 receptor antagonist. These indicate that this Ca2+ mobilization may be regulated by a mechanism independent of a PLC-mediated phosphatidylinositol signaling pathway.
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PMID:Regulation of the potassium current and cytosolic Ca2+ release induced by 2-methylthio ATP in hippocampal neurons. 856 72

P2 purinoceptor agonists produced whole-cell potassium currents in cerebellar neurons with the order of potency 2-methylthio ATP (2-MeSATP) > ADP > ATP > adenosine > alpha,beta- methylene ATP > AMP > UTP. In the outside-out patch clamp configuration, 2-MeSATP evoked single channel currents with two major classes of slope conductances without latency. The currents were blocked by a G-protein inhibitor, GDP beta S, although they were not affected by a phospholipase C inhibitor, a selective protein kinase C or A inhibitor. In contrast, a potent G-protein activator, GTP gamma S, produced single channel currents with same conductances as those of the currents induced by 2-MeSATP. These provide an indication that the P2 purinoceptor-operated potassium channel is regulated by the beta gamma subunits of a G-protein.
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PMID:P2 purinoceptor-operated potassium channel in rat cerebellar neurons. 857 78

ADP evoked outwardly rectifying potassium currents with a latency of 0.6 s in cultured rat medullar neurons. Purinoceptor agonists, such as 2-methylthio ATP (2-MeSATP), ATP, AMP, alpha,beta-methylene ATP (alpha,beta-MeATP), and UTP, produced similar outward currents with the order of their potencies for current amplitudes: 2-MeSATP > ADP > ATP > or = alpha,beta-MeATP > or = AMP > UTP. This order corresponds to that for a subtype of P2Y purinoceptors. ADP-evoked currents were fully blocked by a broad G-protein inhibitor, guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), whereas a G(i)/G(o)-protein inhibitor, pertussis toxin (PTX) had no effect. The currents were not affected by a phospholipase C (PLC) inhibitor, neomycin. Furthermore, a selective protein kinase C inhibitor, GF109203X or a selective cAMP-dependent protein kinase inhibitor, H-89 showed no effect on the currents. These results suggest that ADP activates the potassium channel via a P2Y purinoceptor linked to a PTX-insensitive G-protein and its channel regulation may be due to a direct action of the G-protein beta gamma subunits regardless of second messenger signaling cascades. Additionally, ADP enhanced intracellular free Ca2+ concentration ([Ca2+]i) both in the presence and absence of extracellular calcium, and this [Ca2+]i increase was not inhibited by neomycin. This provides an additional evidence that ADP binds to a subtype of P2Y purinoceptors, which is not involved in PLC stimulation.
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PMID:A P2 purinoceptor activated by ADP in rat medullar neurons. 859 44

The insulin secretory responses of islets isolated from ob/ob mice or their lean litter mates to glucose or the phorbol ester tetradecanoyl phorbol acetate were determined. Glucose-induced phospholipase C activation was also monitored. Even though lean mouse islets contained more insulin than ob/ob mouse islets, the first and second phases of 15mM glucose-induced secretion were significantly greater from ob/ob mouse islets. The kinetics of this amplified response were similar to those seen from lean islets as was the ability of 15mM glucose to activate phospholipase C. A striking dichotomy in responsiveness to the protein kinase C activator tetradecanoyl phorbol acetate was observed between lean and ob/ob mouse islets: while islets from lean animals were unresponsive to tetradecanoyl phorbol acetate (500nM), a rising and sustained insulin secretory response was evoked from ob/ob mouse islets. The combination of 7.5mM glucose plus tetradecanoyl phorbol acetate resulted in dramatic and sustained insulin secretory responses from ob/ob mouse islets, responses that could be duplicated by stimulation with the combination of 3mM glucose, 500nM tetradecanoyl phorbol acetate and 30mM potassium. Significantly smaller responses to these agonist combinations were observed from lean mouse islets. These findings demonstrate that the sensitivity of ob/ob mouse islet protein kinase C to stimulation is markedly enhanced when compared to islets from lean mice and that the activation of protein kinase C or processes distal to and dependent on the enzyme may account, at least in part, for the amplified insulin secretory responses of these islets.
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PMID:Signal transduction in isolated islets from the ob/ob mouse: enhanced sensitivity of protein kinase C to stimulation. 868 45

Cardiac Na+,Ca2+ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate (ATP) but is not mediated by protein kinases. In giant cardiac membrane patches, ATP acted to generate phosphatidylinositol-4,5-bisphosphate (PIP2) from phosphatidylinositol (PI). The action of ATP was abolished by a PI-specific phospholipase C (PLC) and recovered after addition of exogenous PI; it was reversed by a PIP2-specific PLC; and it was mimicked by exogenous PIP2. High concentrations of free Ca2+ (5 to 20 microM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca2+ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP2. ATP-inhibited potassium channels (KATP) were also sensitive to PIP2, whereas Na+,K+ pumps and Na+ channels were not. Thus, PIP2 may be an important regulator of both ion transporters and channels.
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PMID:Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. 868 80

Angiotensin II stimulates DNA synthesis in aortic smooth muscle cells prepared from spontaneously hypertensive rats, with maximal levels detected 20 h after stimulation. Angiotensin II receptor antagonists inhibited the angiotensin II-induced DNA synthesis. In particular, the noncompetitive antagonist 2-ethoxy-1-[[2'(1 H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV11974) was more effective than expected from its affinity for the angiotensin II receptor and its potency for inhibiting angiotensin II-induced increase in cytosolic free Ca2+ concentration 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl]imidazole, potassium salt (losartan), one of the antagonists, inhibited angiotensin II-induced DNA synthesis by 92% and 79%, even when added 2 and 4 h after angiotensin II stimulation, respectively. Angiotensin II also increases the mRNA of platelet-derived growth factor-A chain and basic fibroblast growth factor. The increase was observed within 4 h after angiotensin II stimulation. In this case, the addition of losartan at 4 h after angiotensin II stimulation hardly influenced the time course of the mRNA level of growth factors. Also, conditioned media of cells stimulated with angiotensin II did not influence DNA synthesis in the presence of CV11974. These results suggest that sustained receptor stimulation with angiotensin II is required for DNA synthesis in addition to the early intracellular signaling following phospholipase C activation in a manner independent of the induction of growth factors such as platelet-derived growth factor-AA and basic fibroblast growth factor.
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PMID:A long-term receptor stimulation is requisite for angiotensin II-dependent DNA synthesis in vascular smooth muscle cells from spontaneously hypertensive rats. 871 28


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