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)

It has been hypothesized on the basis of studies on BC3H-1 myocytes that diacylglycerol generation with activation of protein kinase C (PKC) is involved in the stimulation of glucose transport in muscle by insulin (Standaert, M. L., Farese, R. V., Cooper, R. D., and Pollet, R. J. (1988) J. Biol. Chem. 263, 8696-8705). In the present study, we used the rat epitrochlearis muscle to evaluate the possibility that PKC activity mediates the stimulation of glucose transport by insulin in mammalian skeletal muscle. Phospholipase C from Clostridium perfringens (PLC-Cp), which generates diacylglycerol from membrane phospholipids, and 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) induced increases in glucose transport activity (assessed using 3-O-methylglucose transport) that were approximately 80 and approximately 20% as great, respectively, as that induced by a maximal insulin stimulus. PLC-Cp and PMA both caused a approximately 2-fold increase in membrane-associated PKC activity. In contrast, insulin did not affect PKC activity. These findings argue against a role of diacylglycerol-mediated PKC activation in the stimulation of skeletal muscle glucose transport by insulin. They also show that the BC3H-1 myocyte is not a good model for studying regulation of glucose transport in skeletal muscle. Neither the submaximal nor maximal effects of PLC-Cp and insulin on glucose transport were additive, suggesting that PLC-Cp interferes with insulin action. The maximal effects of PLC-Cp and hypoxia or muscle contractions were also not additive. However, the submaximal effects of hypoxia and PLC-Cp were completely additive. These findings raise the possibility that PLC-Cp stimulates glucose transport by the exercise/hypoxia-activated, not the insulin-activated, pathway in skeletal muscle. Exposure to PLC-Cp activated glycogen phosphorylase and potentiated twitch tension in response to electrical stimulation, providing evidence that PLC-Cp increases cytoplasmic Ca2+ concentration. Dantrolene, an inhibitor of Ca2+ release from the sarcoplasmic reticulum, completely blocked both the activation of phosphorylase and the stimulation of glucose transport by PLC-Cp. These findings provide evidence that an increase in cytoplasmic Ca2+ concentration is involved in the activation of glucose transport in skeletal muscle by PLC-Cp.
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PMID:Activation of glucose transport in skeletal muscle by phospholipase C and phorbol ester. Evaluation of the regulatory roles of protein kinase C and calcium. 260 81

Activation of vascular smooth muscle by angiotensin II results in the phospholipase C-mediated generation of two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). IP3 is responsible for mobilizing calcium from endoplasmic reticulum whereas DG activates protein kinase C and ultimately Na+/H+ exchange, leading to intracellular alkalinization. The IP3/calcium signal is transient, most likely serving to initiate calcium-mediated events leading to contraction, and is attenuated by activation of protein kinase C. DG formation/protein kinase C activation is sustained and may be enhanced by the concurrent intracellular alkalinization. The delay in induction of the sustained response appears to be related to cellular processing of the angiotensin II-receptor complex. Phospholipase C activity is also modulated by a cholera toxin-sensitive, pertussis toxin-insensitive guanine nucleotide regulatory protein. This guanine nucleotide regulatory protein, movement of the receptor-ligand complex, and the signals generated by the two second messengers, IP3 and DG, interact in a complex manner to cause an integrated response of vascular smooth muscle to angiotensin II stimulation.
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PMID:Angiotensin II stimulation of vascular smooth muscle cells. Secondary signalling mechanisms. 267 2

We report that a 100 residue segment in the carboxy-terminus half of phosphatidylinositol-specific phospholipase C is similar to a segment in the amino-terminus half of protein kinase C. The computer-based comparison score is 9.5 standard deviations higher than that of 2500 comparisons of randomized sequences of these segments (P = 10(-21), suggesting that the two segments have similar biological properties. Phospholipase C has a segment that is homologous to part of the non-catalytic domain of src kinase and other tyrosine protein kinases. The similarity of phospholipase C with protein kinase C, a serine/threonine kinase suggests that novel exon shuffling occurred among serine/threonine and tyrosine kinases and phospholipase C.
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PMID:Similarity between phospholipase C and the regulatory domain of protein kinase C. 274 13

We studied the cholinergic stimulation of isolated and enriched rat parietal cells. H+ production was indirectly measured by the uptake of 14C-aminopyrine into the parietal cells. Stimulation by carbachol required the presence of extracellular Ca2+ not only in the initial phase but also during the sustained phase of a 100-min incubation period. The response to carbachol was prevented by the Ca2+ entry blocker lanthanum IC50: 1.5 X 10(-7) mol/l). Furthermore, the dependence on Ca2+ influx of cholinergic stimulation was demonstrated by a 269% increase in total intracellular Ca2+ in response to carbachol, as determined by optical emission spectrometry. The naphthalene sulfonamides W7 and W5 which bind calmodulin and thus block the intracellular transduction of Ca2+ effects also inhibited a carbachol-induced H+ production. In the following experiments we studied the effect of agents which activate the protein kinase C, an enzyme which is supposed to play a key role in intracellular signal transduction of Ca2+-dependent effects. Phospholipase C is supposed to activate protein kinase C via induction of the phosphoinositol breakdown. In our preparation of isolated rat parietal cells, phospholipase C (4-100 mU/ml) exerted inhibition instead of amplification of the response to 10(-4) mol/l carbachol. Similarly, the direct activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate or by 1-oleoyl-2-acetyl-sn-glycerol (both tested at 10(-7) to 10(-5) mol/l) reduced the submaximal and maximal response to 10(-5) or 10(-4) mol/l carbachol. We conclude that the cholinergic stimulation of rat parietal cells is dependent on the influx of extracellular Ca2+. Calmodulin seems to mediate intracellular Ca2+ effects during cholinergic stimulation. The activation of protein kinase C impairs carbachol-induced H+ production instead of augmenting the response. This might be due to an already maximal activation of protein kinase C by carbachol alone or to autoregulatory down-regulation by the protein kinase C of muscarinic parietal-cell receptors.
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PMID:Cholinergic stimulation of isolated rat parietal cells: role of calcium, calmodulin and protein kinase C. 280 65

Exposure of isolated SENCAR mouse epidermal cells to the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) in vitro resulted in the production of oxidant species detected as chemiluminescence. This oxidant response can be inhibited by superoxide dismutase and copper complexes but not catalase or scavengers of hydroxyl radical or singlet oxygen, suggesting that the oxidant is superoxide anion. Inhibitors of various parts of the arachidonate cascade affect the TPA-induced oxidant response in a manner that corresponds to their effects on in vivo tumor promotion experiments. Agents that inhibit lipoxygenase activity, i.e. nordihydroguaiaretic acid, benoxaprofen, but not agents that are cyclooxygenase inhibitors, i.e. indomethacin, are effective in suppressing the oxidant response to TPA. Phospholipase C but not phospholipase A2 or D produced an oxidant response kinetically similar to that elicited by TPA. The inhibitors of TPA-induced oxidants inhibited the phospholipase C response to the same extent, suggesting that TPA and phospholipase C may produce an oxidant species through a common mechanism, via phospholipid turnover-protein kinase C activation. The relevance of oxidant production to the tumor promotion process is suggested by the ability of exogenous xanthine/xanthine oxidase, a superoxide anion-generating system, to induce ornithine decarboxylase, a characteristic of TPA-treated cells. In addition, oxidant production is significantly lower in cells from the TPA-promotion resistant C57BL/6J mouse. These studies provide further support for a role for reactive oxygens in the tumor promotion process.
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PMID:Reactive oxygen in the tumor promotion stage of skin carcinogenesis. 284 22

Ca2+ is now recognized to play a central role in the cellular signal transduction system. The hydrolysis of inositol phospholipids is an initial and essential event in Ca2+-mobilizing receptor activation. Phospholipase C cleaves phosphatidylinositol 4,5-bisphosphate to yield two intracellular messengers: inositol 1,4,5-trisphosphate that mobilizes Ca2+ from intracellular storage sites, and 1,2-diacylglycerol that activates protein kinase C. In this chapter, I will describe the functional role of phosphoinositide breakdown during receptor activation and the regulatory mechanism of phospholipase C.
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PMID:Phosphoinositide turnover and calcium ion mobilization in receptor activation. 285 17

Many hormones, neurotransmitters, and secretagogues act by increasing the intracellular free Ca2+ concentration in target cells. The initial event following binding of agonists to specific receptors in the plasma membrane involves a receptor-mediated activation of a guanosine nucleotide-binding protein (G protein), which induces a Ca2+-independent activation of phospholipase C. This novel, presently uncharacterized G protein is inactivated by pertussis toxin-catalyzed adenosine 5'-diphosphate ribosylation in some but not all cell types. Phospholipase C catalyzes the breakdown of inositol lipids, notably phosphatidylinositol 4,5-bisphosphate, with the production of inositol phosphates and 1,2-diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) is responsible for a rapid mobilization of intracellular Ca2+ by activating Ca2+ efflux from a subpopulation of the endoplasmic reticulum. The properties of this process are consistent with its being a ligand-activated ion channel with electrogenic Ca2+ efflux being charge-compensated by K+ influx. Sustained hormonal responses require extracellular Ca2+ and a prolonged elevation of the cytosolic free Ca2+. This is brought about by hormone-mediated changes of Ca2+ flux across the plasma membrane involving both an inhibition of Ca2+ efflux and an activation of Ca2+ influx. This review summarizes recent findings concerning the role of G proteins in receptor coupling to phospholipase C; the regulation of enzymes of phosphoinositide metabolism; the evidence for IP3 being a Ca2+-mobilizing second messenger and its mechanism of action; the formation of new inositol phosphates and their possible significance; the relation of intracellular Ca2+ mobilization and plasma membrane Ca2+ fluxes to the kinetics of the hormone-induced cytosolic free Ca2+ transient; and the possible roles of protein kinase C in influencing the hormone-mediated functional response.
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PMID:Role of inositol lipid breakdown in the generation of intracellular signals. State of the art lecture. 301 67

Studies have been performed on the biochemical mechanism of platelet activation induced by the fibrinolytic protease plasmin. In washed human platelets, greater than or equal to 1.0 caseinolytic units (CU/ml plasmin induced aggregation. Platelet [14C]serotonin release was stimulated by 1.0 CU/ml plasmin to an extent comparable to that induced by 1.0 U/ml thrombin. A dose- and time-dependent phosphorylation of the platelet 47,000- and 20,000-kD proteins was noted in 32PO4-labeled platelets incubated with plasmin; phosphorylation was not affected by extracellular Ca2+, but was completely inhibited by an increase in platelet cyclic AMP. Phosphorylation of these platelet proteins suggested that plasmin may act on platelets by stimulating a rise in cytosolic calcium concentration ([Cai2+]) and activating inositol phospholipid-dependent phospholipase C and protein kinase C. Using both quin2 fluorescence and aequorin luminescence as indicators, plasmin was found to elevate platelet [Cai2+] in the presence or absence of extracellular Ca2+. Phospholipase C activation was shown by the generation of [3H]diglyceride in [3H]arachidonic acid-labeled platelets and [32P]phosphatidic acid in 32PO4 labeled platelets exposed to plasmin. Plasmin did not induce formation of thromboxane A2 (TXA2). Only small amounts of this eicosanoid were detected late in the time course after plasmin stimulation. Our results indicate that plasmin causes platelet aggregation and secretion associated with phosphorylation of the 47,000- and 20,000-kD proteins, Ca2+ mobilization, and phospholipase C and protein kinase C activation.
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PMID:Platelet protein phosphorylation, elevation of cytosolic calcium, and inositol phospholipid breakdown in platelet activation induced by plasmin. 301 42

Evidence exists that a norepinephrine/prostaglandin E2 (PGE2)/cAMP pathway is involved in the regulation of luteinizing hormone-releasing hormone (LHRH) secretion. The aim of the present experiments was to determine if release of LHRH from the immature rat hypothalamus could also be stimulated by activation of protein kinase C. Median eminences from 28-day-old female rats were incubated in vitro with either dioctanoylglycerol (a synthetic diacylglycerol that selectively activates protein kinase C in intact cells) or 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (another protein kinase C activator). Both agents increased LHRH release, the response to dioctanoylglycerol being more pronounced than that to the phorbol ester. This direct activation of protein kinase C was not accompanied by changes in PGE2 formation. Activation of the PGE2/cAMP pathway by either norepinephrine, PGE2, or forskolin (a stimulator of adenylate cyclase) increased LHRH release. Dioctanoylglycerol or phorbol ester in conjunction with either norepinephrine, PGE2 or forskolin resulted in an additive effect on LHRH release suggesting coexistence of both pathways. Phospholipase C, which activates protein kinase C via formation of diacylglycerol, increased the release of both LHRH and PGE2. This suggests that an increase in endogenous phospholipase C activity caused by neurotransmitter inputs may lead to both activation of protein kinase C and PGE2 formation. Blockade of cyclooxygenase activity by indomethacin obliterated phospholipase C-induced PGE2 release. The same treatment reduced the LHRH response by only 50% indicating that protein kinase C activation can cause LHRH release in the absence of PGE2 synthesis. It is suggested that the median eminence of the rat possesses a protein kinase C-dependent pathway that is coupled positively to LHRH release and complements PGE2/cAMP-dependent mechanisms. Norepinephrine, however, does not appear to be the neurotransmitter responsible for activating the protein kinase C pathway. Simultaneous activation of both pathways may provide a mechanism by which a large increase in LHRH secretion occurs, such as in the afternoon of first proestrus.
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PMID:Activation of two different but complementary biochemical pathways stimulates release of hypothalamic luteinizing hormone-releasing hormone. 301 21

Phorbol esters and n-butyrate (SB) together could induce Epstein-Barr virus (EBV) DNA polymerase and DNase activities in Raji cells (virus nonproducer). Neither 12-O-tetradecanoylphorbol-13-acetate (TPA) nor SB alone could induce these EBV enzyme activities, transcription of the EcoRI C-region or other EBV proteins in Raji cells. The enzyme induction caused by exposure of Raji cells to TPA-SB was the result of the synthesis of virus-specified RNA, and the increase of linear EBV DNA content in Raji cells caused by TPA alone was not sufficient for induction of EBV-enzyme activities. Temporal characteristics of the TPA-SB induction process, but not the phorbol 12,13-dibutyrate-SB induction process, in Raji cells were observed; a critical phase (10-24 h) postphorbol ester treatment in phorbol 12,13-dibutyrate-SB-treated Raji cells which was responsible for the synthesis of virus RNA and enzymes was found. Phospholipase C, which increases intracellular diacylglycerols (and subsequently activates protein kinase C) was able to partially substitute for TPA in the TPA-SB induction for EBV polymerase and DNase activities. Sphingosine, a protein kinase C inhibitor, partially prevented the induction of virus enzyme activities in Raji cells treated with phorbol 12,13-dibutyrate and SB. No apparent changes in the methylation state of EBV DNA (EcoRI C region) were observed when Raji cells were treated with SB and TPA, alone or in combination. These results suggest that induction of EBV polymerase and DNase activities by TPA-SB may involve protein kinase C activation and another factor triggered by SB which together increase transcription of EBV DNA.
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PMID:Induction of virus enzymes by phorbol esters and n-butyrate in Epstein-Barr virus genome-carrying Raji cells. 303 11


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