Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. 32P-Labeled proteins from the superior cervical ganglion of the rat were separated by two-dimensional gel electrophoresis and visualized by autoradiography. 2. The most heavily labeled phosphoprotein in the ganglion had a relative molecular weight of 83,000 and a pI of 4.5. Phosphorylation of this protein was increased by phorbol 12,13-dibutyrate, an activator of the Ca2+/phospholipid-dependent protein kinase, protein kinase C. This protein appears to be similar or identical to a specific protein kinase C substrate that has been described in other tissues (Blackshear, P. J., et al., J. Biol. Chem. 261:1459-1469, 1986). 3. Phosphorylation of this protein was also increased by treatment of the ganglion with phospholipase C (Bacillus cereus) but was not increased by 8-bromo-cyclic AMP or by nicotinic agonists. Vasopressin increased the hydrolysis of inositol-containing phospholipids in the ganglion and also increased the labeling of the 83,000 Mr protein. Thus, vasopressin appears to activate protein kinase C in the ganglion. 4. Muscarine, which also increased phospholipid metabolism in the ganglion, did not increase the phosphorylation of the 83,000 Mr protein. Muscarine and vasopressin stimulate phospholipid metabolism in different structures within the ganglion (Horwitz, J., et al., J. Pharmacol. Exp. Ther. 237:312-317, 1986). Muscarine may increase phospholipid metabolism in structures that do not contain significant amounts of the 83,000 Mr protein.
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PMID:Vasopressin stimulates the phosphorylation of an 83,000 Mr protein in the superior cervical ganglion. 345 98

Vasopressin increased intracellular free calcium concentration [Ca2+]i in quin-2-loaded quiescent Swiss 3T3 cells. This effect of vasopressin was rapidly inhibited by biologically active tumour promoters including phorbol dibutyrate (PBt2) and by the synthetic diacylglycerol 1-oleoyl-2-acetyl-glycerol (OAG). Prolonged pretreatment of Swiss 3T3 cells with PBt2 causes a loss of protein kinase C activity (Rodriguez-Pena & Rozengurt, Biochem biophys res commun 120 (1984) 1053) [28]. This pretreatment abolished the inhibition by PBt2 or OAG of vasopressin-mediated increases in [Ca2+]i. Vasopressin also stimulated 45Ca2+ efflux from cells pre-loaded with the isotope. This effect of the hormone was also inhibited by PBt2. Prolonged pretreatment with PBt2 prevented the inhibition of vasopressin-stimulated 45Ca2+ release by PBt2. Thus, protein kinase C stimulation inhibits vasopressin-mediated increases in [Ca2+]i and 45Ca2+ efflux apparently by blocking the increased release of Ca2+ from an intracellular store caused by the hormone. These findings suggest that activation of protein kinase C may act as a feedback inhibitor to modulate ligand-mediated increases in [Ca2+]i.
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PMID:Phorbol esters and diacylglycerol inhibit vasopressin-induced increases in cytoplasmic-free Ca2+ and 45Ca2+ efflux in Swiss 3T3 cells. 345 89

Vasopressin and adrenaline in combination exert synergistic effects on platelet activity. This study investigated the effects of sub-threshold concentrations of adrenaline (0.1-1 microM) on vasopressin (10 nM-1 microM)-induced platelet aggregation, ATP secretion, elevation of cytosolic free Ca2+ concentration ([Ca2+]i) and hydrolysis of inositol phospholipids, monitored as [32P]phosphatidic acid formation. Potentiation of vasopressin-induced aggregation and ATP secretion by adrenaline was accompanied by enhanced elevation of [Ca2+]i and [32P]phosphatidic acid formation. The stimulatory effects of adrenaline on vasopressin-induced platelet activation were mimicked by the combination of the Ca2+ ionophore, ionomycin, and the protein kinase C activator, phorbol 12-myristate 13-acetate, but not by either of these agents alone. These results suggest that the potentiation of vasopressin-induced platelet activation by adrenaline is mediated via enhancement of inositol phospholipid hydrolysis and elevation of [Ca2+]i.
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PMID:Possible mechanisms of the potentiation of blood-platelet activation by adrenaline. 359 15

Release of P-choline and choline from purified rat plasma membrane preparations was increased by GTP and its less hydrolyzable analogues, whereas other nucleotide triphosphates had little or no effect. Stimulation by guanosine 5'-(3-O-thiol)triphosphate (GTP gamma S) was dependent upon magnesium, inhibited by guanosine 5'-(2-O-thiol)diphosphate, and independent of calcium. ATP and ADP (1-100 microM) markedly enhanced the GTP gamma S stimulation of P-choline plus choline release but had no effect alone. ADP was as effective as ATP and nonhydrolyzable ATP analogues produced a similar or greater stimulation, whereas AMP and adenosine were much less effective. Vasopressin (0.1 microM) also produced a small stimulation. Under conditions in which protein kinase C was activated, PMA also stimulated the response to GTP gamma S but was ineffective in its absence. P-choline was the initial product which was hydrolyzed to choline. Guanine nucleotide and purinergic effects were also apparent on phosphatidylcholine degradation. EGTA, at 0.5 mM, completely removed purinergic stimulation but did not affect P-choline plus choline released in response to GTP gamma S alone. Prior treatment of plasma membranes with cholera toxin or prior injection of animals with islet-activating protein did not affect the stimulation of P-choline plus choline release either by GTP gamma S alone or by GTP gamma S plus ATP. These results indicate that a phosphatidylcholine phospholipase C is coupled to purinergic receptors in rat liver plasma membranes by a GTP-binding protein. Hydrolysis of phosphatidylcholine could contribute to hepatic diacylglycerol levels and thus influence protein kinase C activity.
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PMID:Phosphatidylcholine breakdown in rat liver plasma membranes. Roles of guanine nucleotides and P2-purinergic agonists. 381 51

Vasopressin stimulated gluconeogenesis from proline in hepatocytes from starved rats; this was attributed to an activation of oxoglutarate dehydrogenase (EC 1.2.4.2) [Staddon & McGivan (1984) Biochem. J. 217, 477-483]. The role of Ca2+ in the activation mechanism was investigated. (1) In the absence of extracellular Ca2+, vasopressin caused a stimulation of gluconeogenesis and a decrease in cell oxoglutarate content that were markedly transient when compared with the effects in the presence of Ca2+. (2) Ca2+ added to cells stimulated for 2 min by vasopressin in the absence of extracellular Ca2+ sustained the initial effects of vasopressin. Ca2+ added 15 min after vasopressin, a time at which both the rate of gluconeogenesis and the cell oxoglutarate content were close to the control values, caused a stimulation of gluconeogenesis and a decrease in cell oxoglutarate content. (3) Under conditions of cell-Ca2+ depletion, vasopressin had no effect on gluconeogenesis or cell oxoglutarate content. (4) Ionophore A23187 stimulated gluconeogenesis and caused a decrease in cell oxoglutarate content, but the phorbol ester 4 beta-phorbol 12-myristate 13-acetate had no effects. (5) These data suggest that the initial activation of oxoglutarate dehydrogenase by vasopressin is dependent on an intracellular Ca2+ pool and independent of extracellular Ca2+. For activation of a greater duration, a requirement for extracellular Ca2+ occurs. The activation of oxoglutarate dehydrogenase by A23187 is consistent with a mechanism involving Ca2+, but the lack of effect of 4 beta-phorbol 12-myristate 13-acetate indicates that protein kinase C is not involved in the mechanism of activation by vasopressin.
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PMID:Ca2+-dependent activation of oxoglutarate dehydrogenase by vasopressin in isolated hepatocytes. 391 5

Hormones that elevate cytosolic Ca2+ concentrations ([Ca2+]cyt) often use Ca2+ as a messenger to activate intramitochondrial metabolic processes. However, the mitochondrial Ca2+ level also regulates the activation of the mitochondrial permeability transition (MPT), a process that involves the assembly of a high conductance proteinaceous pore across the inner and outer membrane. Studies on intact liver cells indicate that the MPT is a critical step in the cell killing induced by anoxia or respiratory inhibitors. In this study, we used freshly isolated hepatocytes to investigate to what extent the elevation of [Ca2+]cyt by vasopressin or other agonists causes Ca2+ accumulation in the mitochondria and how this treatment affects the mitochondrial susceptibility to undergo the MPT. Hepatocytes were incubated with vasopressin, glucagon, or with thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ pump) prior to permeabilization with digitonin. Mitochondrial Ca2+ accumulation was determined by following the ionomycin-induced Ca2+ release in permeabilized cells and mitochondrial swelling was studied by following cyclosporin A-sensitive light scattering changes induced by phenyl-arsenoxide and rotenone. The results indicate that agents that elevate [Ca2+]cyt cause a significant Ca2+ accumulation in the mitochondria. Excessive Ca2+ accumulation (> 10-fold increase over basal levels) was obtained with the combination of vasopressin and glucagon or with incubations containing thapsigargin. These conditions were also associated with a marked increase in rotenone-induced mitochondrial swelling. However, the more modest increase in mitochondrial Ca2+ content after treating cells with vasopressin alone did not enhance the swelling response; instead, vasopressin suppressed mitochondrial swelling compared to control incubations. Vasopressin also partly suppressed the swelling associated with thapsigargin treatment, although it did not significantly affect the Ca2+ accumulation under these conditions. This effect of vasopressin was mimicked by phorbol ester, suggesting a role for protein kinase C. The data indicate that mitochondrial Ca2+ accumulation following elevation of elevation of [Ca2+]cyt enhances the susceptibility for activation of the MPT, a response that may increase cell injury during anoxia or in response to other challenges. However, hormones also activate protective responses in the cell that suppress the MPT.
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PMID:Calcium ion-dependent signalling and mitochondrial dysfunction: mitochondrial calcium uptake during hormonal stimulation in intact liver cells and its implication for the mitochondrial permeability transition. 759 32

Both protein kinase C and cytosolic Ca2+ are involved in the regulation of exocytosis in a number of cell types. However, the relative importance of each of these for apical exocytosis in the hepatocyte is unknown. To investigate this, we studied the effects of protein kinase C and Ca2+ agonists on horseradish peroxidase excretion in the isolated perfused rat liver. Vasopressin increased both horseradish peroxidase concentration and net horseradish peroxidase excretion in bile, and these effects were abolished by the protein kinase C inhibitor H-7. The protein kinase C activator phorbol dibutyrate also increased both net excretion and the concentration of biliary horseradish peroxidase. In contrast, the Ca2+ ionophore A23187 and the Ca2+ mobilizing agent 2,5'-di(tertbutyl)-1,4-benzohydroquinone both had minimal effects on horseradish peroxidase concentration and inhibited the rate of horseradish peroxidase excretion. These results suggest that protein kinase C stimulates apical exocytosis in the hepatocyte, whereas increased Cai2+ per se does not influence exocytosis and inhibits excretion only transiently by reducing bile flow.
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PMID:Effects of protein kinase C and cytosolic Ca2+ on exocytosis in the isolated perfused rat liver. 792 5

Arginine vasopressin mediates its effects through vasopressin receptor activation and second messenger production. Recent cloning of the V1a receptor provided the opportunity to investigate the possible signal transduction pathways associated with this single vasopressin receptor subtype. When stably expressed in CHO cells, vasopressin stimulated several signal transduction pathways simultaneously including calcium influx, phospholipase A2, phospholipase C, and phospholipase D. Vasopressin-stimulated release of arachidonic acid, IP3 formation, and phosphatidylethanol formation (in the presence of 1% ethanol) were used as indexes of phospholipase A2, phospholipase C, and phospholipase D activation, respectively. V1a receptor-activation stimulated a peak followed by a sustained plateau phase of intracellular calcium. The plateau phase was dependent on extracellular calcium, insensitive to blockers of voltage sensitive calcium channels, blocked by heavy metals, and quenched when MnCl2 was present in the extracellular media. Removal of extracellular calcium blunted the release of IP3, and blocked the release of arachidonic acid and phosphatidylethanol indicating that these responses were at least in part regulated by receptor-operated calcium influx. Vasopressin-stimulated release of arachidonic acid and phosphatidylethanol were augmented with the phorbol ester PMA, and this augmentation was blocked by inhibitors of protein kinase C and absent with long-term PMA treatment. Vasopressin-stimulated IP3 release was inhibited with PMA and the inhibition reversed with protein kinase C inhibitors.
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PMID:The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. 796 20

The regulation of transport in the collecting duct is under multi-hormonal control. Vasopressin stimulates water and cation transport, primarily through a V2/Gs-coupled receptor that activates adenylyl cyclase, which raises cAMP. These stimulatory effects are damped by the action of several hormones, including vasopressin itself, which activate inhibitory G proteins, stimulate phospholipid breakdown, increase prostaglandin production, raise intracellular Ca2+, activate protein kinase C, stimulate tyrosine kinases, and raise cGMP. These inhibitory signals interact with the stimulatory, cAMP-coupled signaling pathway at multiple levels. The balance between these pathways controls net salt and water transport in the collecting duct.
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PMID:Hormonal signaling and regulation of salt and water transport in the collecting duct. 801 Jul 58

Bile salt uptake by hepatocytes is modulated in part by changes in intracellular cyclic AMP. We studied the effect of activation of protein kinase C on cyclic AMP-mediated taurocholate uptake in isolated rat hepatocytes. Both dibutyryl cyclic AMP (2 x 10(-6) mol/L) and glucagon (10(-6) mol/L), which increase intracellular cyclic AMP, enhanced the initial uptake rate of taurocholate into hepatocytes, with maximal increases of 45% to 50% over the basal uptake rate. Vasopressin (10(-9) mol/L), a hormone known to activate protein kinase C, and phorbol-12,13-dibutyrate (10(-5) mol/L) significantly inhibited the glucagon-stimulated increase in taurocholate uptake rate (72% +/- 10% and 105% +/- 13% inhibition, respectively). Basal (unstimulated) taurocholate uptake rate was not affected by vasopressin or phorbol-12,13-dibutyrate. Down-regulation of the glucagon-stimulated transport was rapid and persisted during the 20-min experimental period. Angiotensin II had a similar but more transient inhibitory effect. Vasopressin and phorbol-12,13-dibutyrate suppression of glucagon-stimulated taurocholate uptake rate was not accompanied by diminished cyclic AMP levels. Moreover, vasopressin and phorbol-12,13-dibutyrate inhibited dibutyryl cyclic AMP-stimulated taurocholate uptake rate can be dissociated from alterations in the cyclic AMP levels.
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PMID:Vasopressin and phorbol-12,13-dibutyrate inhibit glucagon- or cyclic AMP-stimulated taurocholate uptake in isolated rat hepatocytes. 802 Aug 86


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