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)

Integrating flame photometry was used for measuring sodium in single pancreatic islets from ob/ob mice. Exposure to 100 microM carbachol resulted in a 25-40% increase in sodium without any effect on potassium during incubation with 0-5 mM glucose in media deficient or not in Ca2+. This action of carbachol was abolished by 10 microM atropine or by raising the glucose concentration to 20 mM. A minor increase of the steady state content of sodium occurred in the presence of 200 microM ATP or 10 nM tetradecanoylphorbol 13-acetate (TPA). Carbachol differed from TPA in markedly stimulating sodium accumulation after ouabain inhibition of the Na/K pump. The results indicate that muscarinic receptor activation has opposite effects to glucose in inducing a rise of the islet content of sodium. It is suggested that the cholinergic control of the endocrine pancreas involves entry of Na+ in addition to the Na+ entry mediated by protein kinase C activation of Na+/H+ countertransport.
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PMID:Carbachol has opposite effects to glucose in raising the sodium content of pancreatic islets. 180 89

In isolated and enriched guinea-pig gastric mucous cells the effects of carbachol, prostaglandin E2 (PG E2), prostaglandin F2 alpha (PG F2 alpha) and histamine on adenylate cyclase (AC) and cytosolic free Ca2+ were investigated, in order to study the biochemical mechanisms involved in secretagogue-mediated mucus release. Histamine and both prostaglandins stimulated AC in partially purified membranes of mucous cells. Histamine was most efficacious, followed by PG E2 and PG F2 alpha. The histamine effect was blocked by the H2-receptor antagonist ranitidine, but not by the H1-receptor antagonist mepyramine. Carbachol raised the resting [Ca2+]i in mucous cells from 120 to 306 nM. This carbachol effect was blocked by atropine. Histamine and PG E2 stimulation of AC was inhibited in a concentration-dependent manner by Ca2+ (IC50:31 microM). In the presence of TPA and phosphatidylserine, conditions which activate protein kinase C, the inhibitory action of Ca2+ on AC was significantly increased. These data indicate that there exists a negative feedback control mechanism between protein kinase C and histamine/prostaglandin E2-induced AC activation. From the finding that TPA and phosphatidylserine increased the inhibitory action of Ca2+ on cholera toxin-, but not on forskolin-stimulated AC we assume that the point, where protein kinase C exerts its inhibitory effect at the AC, is the guanine nucleotide regulatory protein.
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PMID:Signal transduction pathway in gastric mucous cells. 182 37

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

The mechanisms by which quisqualate and carbachol increase intrasynaptosomal free calcium ([Ca2+]i) were studied in rat cortical synaptosomes. Quisqualate (0.01-100 microM) and carbachol (100-1000 microM) increased [Ca2+]i in Fura-2 acetoxymethyl ester (Fura-2 AM)-loaded synaptosomes. The resting level of [Ca2+]i was 118 nM. The maximum increase (55%) was produced by 10 microM quisqualate which had an EC50 of 0.2 microM. The maximum increase (28%) elicited by carbachol occurred at 1000 microM and the EC50 was 30 microM. The stimulatory effects of quisqualate on [Ca2+]i were blocked by heparin (100 I.U.) but not by staurosporine (1 microM), nifedipine (1 microM) or omega-conotoxin fraction GVIA (omega-CgTx) (0.5 microM). On the other hand, the effects of carbachol on [Ca2+]i were abolished by staurosporine, nifedipine or omega-CgTx but not by heparin. Carbachol (100 microM) also significantly increased 45Ca accumulation into either resting or K+ (30 mM)-depolarised synaptosomes and these effects were inhibited by staurosporine and nifedipine. Quisqualate (10 microM) had no effect on 45Ca accumulation under resting or depolarised conditions. When quisqualate and carbachol were used in combination, there were apparently additive effects on [Ca2+]i but not on 45Ca accumulation. It is concluded that carbachol increases [Ca2+]i by facilitating Ca2+ entry through L-type Ca2+ channels via a 1,2-diacylglycerol (DAG)-protein kinase C (PKC)-dependent pathway while quisqualate mobilizes Ca2+ from inositol 1,4,5-trisphosphate (IP3)-sensitive stores.
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PMID:Quisqualate and carbachol-induced increases in intrasynaptosomal free calcium are mediated by different products of phospholipid hydrolysis. 187 61

Protein kinase C is involved in mediating the effects of elevated Ca2+ in ileal villus Na+ absorbing cells to inhibit NaCl absorption. The present studies were undertaken to understand the mechanism by which this occurs. The effects of carbachol and the calcium ionophore A23187, agents which elevate intracellular Ca2+ and inhibit NaCl absorption in ileal villus cells, were studied. Carbachol treatment of villus cells caused a rapid decrease in protein kinase C activity in cytosol, with an accompanying increase in microvillus membrane C kinase. Exposure of the villus cells to calcium ionophore also caused a quantitatively similar decrease in cytosol C kinase and increase in C kinase activity in the microvillus membrane. This increase caused by carbachol and Ca2+ ionophore was specific for the microvillus membrane. In fact, 30 s and 10 min after exposure of the cells to carbachol, basolateral membrane protein kinase C decreased, in a time-dependent manner; whereas 10 min of Ca2+ ionophore exposure did not alter basolateral C kinase. Exposure of villus cells to Ca2+ ionophore or carbachol caused similar increases in microvillus membrane diacylglycerol content. As judged by the ability to inhibit Na+/H+ exchange measured in ileal villus cell brush border membrane vesicles, the protein kinase C which translocated to the microvillus membrane was functionally significant. Inhibition of Na+/H+ exchange required ATP and was reversed by the protein kinase C antagonist H-7. In conclusion, the effect of carbachol and Ca2+ ionophore in regulation of ileal NaCl absorption is associated with an increase in microvillus membrane diacylglycerol content and functionally active protein kinase C. The effects of both carbachol and Ca2+ ionophore are different on brush border and basolateral membrane distribution of protein kinase C.
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PMID:Carbachol- and elevated Ca(2+)-induced translocation of functionally active protein kinase C to the brush border of rabbit ileal Na+ absorbing cells. 188 73

Carbachol, through a muscarinic receptor, thyrotropin-releasing hormone (TRH), prostaglandin F2 alpha (PGF2 alpha), bradykinin, and adenosine triphosphate (ATP) increased the apparent [Ca2+]i (intracellular free Ca2(+)-concentration) of dog thyrocytes in primary culture. The [Ca2+]i measured by the Quin-2 technique rose immediately after the addition of the agonists and reached a maximal value after less than 30 seconds. Afterwards, the [Ca2+]i declined to a plateau higher than the basal level when the cells were triggered with carbachol. By contrast, in most experiments with PGF2 alpha and in the case of bradykinin, TRH, and ATP, the [Ca2+]i returned to the basal value. If the extracellular Ca2+ was chelated by excess of EGTA, the addition of all agents caused a sharp reduced transient rise in the [Ca2+]i followed by a decline of the [Ca2+]i often below the basal level (especially in the case of carbachol). It is suggested that the first transient phase of these responses is due at least in part to the mobilisation of Ca2+ from intracellular stores whereas the second sustained phase of the response to carbachol mainly originates from an increased Ca2+ influx into the thyrocytes. Carbachol, bradykinin, TRH, PGF2 alpha, and ATP also increased generation of inositol phosphates in dog thyrocytes. This effect was sustained when the cells were triggered with carbachol and was more transient with bradykinin, TRH, PGF2 alpha, or ATP. All these agents and the phorbdester TPA as well as forskolin enhanced to various extent the thyrocyte H2O2 generation. This enhancement was severely reduced in the absence of extracellular Ca2+ and was mimicked by Ca2+ ionophores in the presence of extracellular Ca2+ especially in synergy with protein kinase C activators. These data suggest that the dog thyrocyte H2O2 generation, the limiting step of the thyroid hormone synthesis, is modulated by carbachol, TRH, PGF2 alpha, bradykinin, and ATP through their action on the Ca2(+)-phosphatidylinositol cascade.
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PMID:Control of the intracellular Ca(2+)-concentration and the inositol phosphate accumulation in dog thyrocyte primary culture: evidence for different kinetics of Ca(2+)-phosphatidylinositol cascade activation and for involvement in the regulation of H2O2 production. 199 73

Receptor-mediated arachidonic acid release and its relationship to phospholipase A2 and phospholipase C activation were investigated in Chinese hamster ovary cells transfected with and expressing the m5 muscarinic receptor. Carbachol, a muscarinic receptor agonist, stimulated the release of arachidonic acid and inositol phosphates with similar potencies. In addition, carbachol and the phorbol ester, phorbol-12-myristate, 13-acetate (PMA), stimulated protein kinase C (PKC) activity. PMA potentiated the carbachol-stimulated release of arachidonic acid, but had no effect on release of inositol phosphates. Long-term preincubation with PMA or carbachol inhibited PKC activity and prevented carbachol-stimulated release of arachidonic acid, but not inositol phosphates, suggesting that release of arachidonic acid, but not release of inositol phosphates, required activation of PKC. Carbachol stimulated the release of [3H]lysophosphatidylcholine from [3H]choline prelabeled cells, suggesting that phospholipase A2 was involved in the release of arachidonic acid. The role of calcium in carbachol-stimulated release of arachidonic acid was also investigated. Carbachol stimulated a transient followed by a sustained increase in intracellular calcium. In the absence of extracellular calcium, the transient rise in intracellular calcium was maintained but the sustained increase in intracellular calcium and the release of arachidonic acid were abolished. Carbachol stimulated a sustained influx of 45Ca++. We conclude that the combined effect of PKC activation and sustained elevation of intracellular calcium, from an extracellular source, is essential for m5 muscarinic receptor activation of phospholipase A2.
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PMID:A transfected m5 muscarinic acetylcholine receptor stimulates phospholipase A2 by inducing both calcium influx and activation of protein kinase C. 212 20

Previous work had shown that nicotinic antagonists resulted in a marked up-regulation of alpha-bungarotoxin sites in chromaffin cells in culture. The present experiments were done to determine the intracellular mechanism(s) whereby nicotinic antagonists might mediate their effects on these receptors. Chromaffin cells were cultured for three days with various concentrations of 4 beta-phorbol 12-myristate 13-acetate, an agent which affects protein kinase C by mimicking the actions of diacylglycerol. The phorbol ester resulted in a dose-dependent increase in alpha-bungarotoxin binding which was maximal with 100 nM 4 beta-phorbol 12-myristate 13-acetate. This increase in binding appeared to be due to an increase in the maximal number of alpha-bungarotoxin sites. Time dependence studies showed that the effect of the phorbol was undetectable with incubations of 24 h or less and appeared to plateau by 72-96 h. A similar increase in toxin binding was also observed with 4 beta-phorbol 12,13-dibutyrate. On the other hand, an inactive analog of 4 beta-phorbol 12-myristate 13-acetate had no significant effect on binding. D-Sphingosine, an inhibitor of protein kinase C, was able to partially block the phorbol ester-induced increase in toxin binding while polymyxin B, another protein kinase C inhibitor, completely prevented the up-regulation of the alpha-bungarotoxin sites. Carbachol and nicotine prevented this enhancement of toxin binding in the presence of 4 beta-phorbol 12-myristate 13-acetate. Although the phorbol ester resulted in an increase in toxin binding, acetylcholine-evoked catecholamine secretion from chromaffin cells in culture was decreased, indicating a dissociation between the functional nicotinic acetylcholine receptor population and the alpha-bungarotoxin sites. To determine whether agents which affect protein kinase C can alter the up-regulation of alpha-bungarotoxin sites by d-tubocurarine, 4 beta-phorbol 12-myristate 13-acetate was added to the cells in combination with the nicotinic antagonist. The up-regulation of toxin binding sites induced by d-tubocurarine was additive with that induced by the phorbol and was not affected by polymyxin B. Thus, the results would suggest that there are at least two mechanisms by which alpha-bungarotoxin binding sites can be regulated. One is mediated via an interaction at nicotinic receptors, while the other occurs in response to phorbol esters and thus may be mediated by protein kinase C. Interestingly, although the molecular mechanisms resulting in alpha-bungarotoxin receptor up-regulation differ, both the d-tubocurarine- and the phorbol ester-induced increases were prevented by nicotinic receptor ligands.
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PMID:Phorbol esters and d-tubocurarine up-regulate alpha-bungarotoxin sites in chromaffin cells in culture via distinct mechanisms. 215 30

Acute desensitization of M1 muscarinic receptor-mediated responses (cyclic GMP formation and inositol phosphate release) was studied in murine neuroblastoma cells (N1E-115 clone). After a 45-min incubation at 37 degrees of N1E-115 cells either in monolayer or in suspension, with the muscarinic agonist carbachol (1 mM), the receptor-mediated cyclic GMP response to carbachol was nearly completely lost. This loss was associated with greater than 80% loss of carbachol-mediated inositol phosphate release. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) inhibited both responses with similar potencies. Carbachol or PMA reduced by 30-40% the number of muscarinic receptor sites for antagonist and agonist on intact cells (determined in binding assays using [3H]N-methylscopolamine) only for cells in monolayer and not for those in suspension. PMA but not carbachol pretreatment of cells in monolayer or in suspension caused a translocation of [3H]phorbol 12,13-dibutyrate binding and protein kinase C activity. In addition, desensitization to carbachol occurred in cells largely depleted of protein kinase C by chronic exposure to PMA. Thus, agonist-mediated down-regulation is not needed for muscarinic M1 receptor desensitization, which may be a result of the activation of a receptor-activated kinase different from protein kinase C.
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PMID:Desensitization of muscarinic M1 receptors of murine neuroblastoma cells (clone N1E-115) without receptor down-regulation and protein kinase C activity. 216 77

STa, the heat-stable enterotoxin of Escherichia coli, stimulates membrane-bound guanylate cyclase in enterocytes, elevates cyclic GMP, and results in intestinal secretion of ions and fluid. Using the T84 colon carcinoma cell line as a model. Weikel et al. reported that phorbol esters enhance STa-stimulated cyclic GMP production by 60-140% [(1990) Infect. Immun. 58, 1402-1407]. In the present report we demonstrate that the acetylcholine analog carbachol enhanced toxin-stimulated cyclic GMP accumulation in intact T84 cells by 50-100% and that this effect was blocked by 10 microM atropine and 10 microM sphingosine. Pertussis toxin treatment of the T84 cells did not affect the subsequent response to carbachol. Carbachol, which elevates intracellular calcium in these cells, may act through protein kinase C to enhance cyclic GMP production.
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PMID:Carbachol mimics phorbol esters in its ability to enhance cyclic GMP production by STa, the heat-stable toxin of Escherichia coli. 217 3


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