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. Intracellular pH (pHi) was measured in single rat cerebellar Purkinje cells maintained in primary culture using microspectrofluorescence analysis of the intracellularly trapped pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5 (and -6)-carboxyfluorescein (BCECF). 2. The ratio of the fluorescence signals measured at 530 nm in response to an alternating excitation at 450 and 490 nm was calibrated using the K(+)-H+ ionophore nigericin. This calibration gave a steady-state pHi of 7.06 +/- 0.02 (S.E.M., n = 17) when cells were perfused by a 5% CO2-25 mM-HCO3(-)-buffered solution at an external pH of 7.40 at 37 degrees C. 3. Replacement of external chloride with gluconate in the presence of bicarbonate induced a cytoplasmic alkalinization of about 0.3 pH unit. This alkalinization was independent of external sodium and was greatly reduced by 0.5 mM-DIDS, indicating the presence of a chloride-bicarbonate exchange. 4. In bicarbonate-free (HEPES-buffered) solution the steady-state pHi was 7.37 +/- 0.02 (n = 19), significantly higher than in bicarbonate-buffered solution. Recovery from an intracellular acid load brought about by the ammonium chloride pre-pulse technique was blocked by the removal of external sodium or the addition of 1.5 mM-amiloride, indicating the presence of a sodium-hydrogen exchange. 5. In bicarbonate-buffered solution pHi recovery after an acid load was also completely blocked by addition of 1.5 mM-amiloride indicating the absence of a bicarbonate-dependent acid extrusion mechanism. 6. Addition of 12-O-tetradecanoylphorbol-13-acetate (TPA, 100 nM) induced an amiloride-sensitive alkalinization of about 0.3 pH unit in bicarbonate-buffered solution but had no effect in HEPES-buffered solution. This observation suggests that in cultured Purkinje cells the sodium-hydrogen exchanger could be activated through a protein kinase C pathway only when pHi is maintained at a low physiological value by the activity of the chloride-bicarbonate exchange.
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PMID:Ionic control of intracellular pH in rat cerebellar Purkinje cells maintained in culture. 221 91

The effect of activation of protein kinase C on stimulation of ornithine decarboxylase (ODC) activity and cAMP production was studied in fetal rat osteoblasts. Both phorbol 12-myristate, 13-acetate (PMA), an activator of protein kinase C, and 4 alpha-phorbol, ineffective in activating protein kinase C, failed to stimulate ODC activity and cAMP production. We tested the effect of protein kinase C on stimulation of ODC activity by parathyroid hormone (PTH) and forskolin. In contrast to PTH-stimulated ODC activity, which was not affected by PMA, forskolin-stimulated (1 and 10 microM) ODC activity was dose dependently reduced. PMA (400 nM) reduced both 1 and 10 microM forskolin-stimulated ODC activity to the same level, approximately 3 nmol CO2/mg protein, which suggests a controlling role of protein kinase C in forskolin-stimulated ODC activity. The study of the effect of protein kinase C on PTH- and forskolin-stimulated cAMP production also revealed differences between PTH and forskolin. When PMA was added simultaneously with PTH (4 and 20 nM) or forskolin (1 and 10 microM) the PTH-stimulated cAMP production was dose-dependently potentiated by PMA, whereas forskolin-stimulated cAMP production was not affected. However, both PTH- and forskolin-stimulated cAMP production was dose-dependently augmented when PMA was added 3 min prior to PTH or forskolin. With increasing preincubation periods (up to 24 h) with PMA instead of a potentiation an inhibition was observed. This inhibition is not due to PTH receptor desensitization, although, on basis of the present results desensitization can not completely be excluded. In all cases 4 alpha-phorbol was without effect. The present results show that protein kinase C modulates stimulation of ODC activity and cAMP production in fetal rat osteoblasts. The modulation of both ODC activity and cAMP production appears to be dependent on the nature of the stimulator. The present data suggest a role for protein kinase C in limiting the cAMP-mediated stimulation of ODC activity in these cells. Furthermore, it is suggested that protein kinase C can interfere at more than one site in the cAMP-generating system.
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PMID:Modulatory function of protein kinase C in the activation of ornithine decarboxylase and in cAMP production in rat osteoblasts. 253 85

Very little has been known of the biochemical function of a human adrenocortical carcinoma cell line, SW-13. In this study, the production of several adrenal steroids and 3', 5'-cyclic adenosine monophosphate (cAMP) were investigated in this cell line. The cells were incubated in L-15 medium containing 0.1% bovine serum albumin with several reagents in an atmosphere of 5% CO2 and 95% air for 2 hours at 37 degrees C. Aldosterone (Ald), corticosterone (B), cortisol (F), dehydroepiandrosterone sulfate (DHEA-S) and cAMP were simultaneously assayed by specific radioimmunoassays in the medium and cells. Significant increases in cAMP production were observed by cholera toxin (10 ng/ml) and forskolin (10 nM), both direct stimulators of adenylate cyclase, in the cAMP concentration without an increase in the steroids. The DHEA-S concentration in the medium was significantly increased by angiotensin-II (10(-7)M), noradrenalin (3 X 10(-5) M), adrenalin (3 X 10(-5) M) or alpha-melanocyte-stimulating hormone (alpha-MSH, 10(-7) M), none of which was associated with cAMP production. Neither adrenocorticotropin (10(-10) M) nor human chorionic gonadotropin (500 mIU/ml) stimulated the release of the steroids or cAMP production. A calcium ionophore, A23187 (10(-7) M), and 12-O-tetradecanoylphorbol-13-acetate (10(-8) M), a direct stimulator of protein kinase C, stimulated the release of DHEA-S, but not those of Ald, B and F. The results suggest that SW-13 retains functioning adenylate cyclase which, however, is not linked with steroidogenesis and that DHEA-S is produced probably by the mechanisms which involve protein kinase C system or calcium ion. This report provides the first demonstration of cAMP and DHEA-S production in SW-13 and suggests that this cell line is potentially useful for investigating the mechanisms of steroidogenesis in the human adrenal cortex.
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PMID:Dehydroepiandrosterone sulfate (DHEA-S) and 3', 5'-cyclic adenosine monophosphate (cAMP) production in a cultured human adrenocortical carcinoma cell line (SW-13). 284 Feb 74

The physiological and pathophysiological roles of protein kinase C activation were investigated in cultured mouse myocardial cells. First, effects of 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), a potent activator of protein kinase C, on the intracellular pH (pHi) and cytosolic free Ca2+ level [( Ca2+]i) were studied, using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) and quin-2, respectively. In the presence of the Ca ionophore A23187, TPA induced a rise in pHi by activating amiloride-sensitive Na+/H+ exchange and also produced a rise in [Ca2+]i above that seen with A23187 alone. These effects were totally inhibited by amiloride. Second, the effect of TPA on hypoxia-induced myocardial cell injury was evaluated. The addition of TPA to the culture medium enhanced creatine kinase release from hypoxic myocardial cells (95% N2 + 5% CO2). This effect was markedly suppressed by the addition of amiloride. These data suggests that protein kinase C activation aggravates hypoxic myocardial injury, presumably by inducing Ca2+ overload. This event is secondary to activation of Na+/Ca2+ exchange through accelerated influx of Na+ into the cells as a result of Na+/H+ exchange stimulation by protein kinase C.
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PMID:Protein kinase C activation aggravates hypoxic myocardial injury by stimulating Na+/H+ exchange. 285 Oct 54

A new type of phorbol ester, which has a macrocyclic dicarboxylic acid diester structure, was isolated from the seed oil of Jatropha curcas L. (Euphorbiaceae). Based on the results of spectroscopic analyses of the compound and its chemical degradation products, its structure is proposed to be an intramolecular 13,16-diester of 12-deoxy-16-hydroxyphorbol, 12-deoxy-16-hydroxyphorbol-4'-[12',14'-butadienyl]-6'-[16',18',20' - nonatrienyl]-bicyclo[3.1.0]hexane-(13-O)-2'-[carboxylate]-(16-O)-3 '- [8'-butenoic-10']ate (DHPB). DHPB showed slightly weaker biological and biochemical activities than 12-O-tetradecanoylphorbol-13-acetate (TPA). DHPB induced ornithine decarboxylase in mouse skin (2.8 nmol CO2/30 min/mg protein/34 nmol application), inhibited the specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to phorbol ester receptors (50% effective dose, 17.0 nM), and activated protein kinase C in vitro (50% effective dose, 36.0 nM). Also, a weak tumor-promoting activity of DHPB was found in a two-stage carcinogenesis experiment on mouse skin. One week after initiation of mice with 100 micrograms of 7,12-dimethyl-benz(a)anthracene, topical application, twice a week, of 2 micrograms of DHPB until week 17, followed by application of 5 microgram of DHPB until week 30 at the same rate, resulted in 46.7% incidence of tumors by week 30. The groups treated with 7,12-dimethylbenz(a)anthracene alone or DHPB alone did not produce significant numbers of tumors. These results indicate that the new phorbol ester, DHPB, is a tumor promoter with weaker activity than 12-O-tetradecanoylphorbol-13-acetate.
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PMID:A new tumor promoter from the seed oil of Jatropha curcas L., an intramolecular diester of 12-deoxy-16-hydroxyphorbol. 316 37

Several hormones induce phosphatidylinositol turnover in cell membranes and thus activate protein kinase C. Activation of protein kinase C can, in turn, have effects on epithelial transport. These experiments were designed to investigate the effects of two activators of protein kinase C, phorbol 12-myristate,13-acetate (PMA) and L-alpha-1,2-dioctanoylglycerol (L-alpha-1,2-DOG), and two inactive analogues, 4 alpha-phorbol and 4-O-methyl phorbol 12-myristate,13-acetate, on sodium, potassium, chloride, and total CO2 transport in the rabbit cortical collecting tubule. Utilizing in vitro microperfusion techniques, we found that activation of protein kinase C with either PMA or L-alpha-1,2-DOG significantly inhibited net sodium absorption, net potassium secretion and transepithelial voltage in a dose-dependent manner. There was no effect on net chloride or total CO2 transport. In contrast, the inactive phorbol analogues did not alter either sodium or potassium transport. These studies demonstrate that in the rabbit cortical collecting tubule sodium and potassium transport can be inhibited by compounds known to activate proteins kinase C. Thus, hormones that induce phosphatidylinositol turnover in the rabbit cortical collecting tubule may lead to inhibition of sodium transport by activation of protein kinase C.
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PMID:Effects of protein kinase C activation on sodium, potassium, chloride, and total CO2 transport in the rabbit cortical collecting tubule. 368 May 14

Macaque sperm require treatment with dibutyryl cAMP (dbcAMP) and caffeine (termed activators; ACT) to fully capacitate in vitro. Previous studies have shown that treatment with ACT also increases sperm binding to the macaque zona pellucida and enhances the induction of acrosome reactions of the bound sperm. This study investigated whether phorbol 12-myristate 13-acetate (PMA) and 1,2-dioctanoyl-sn-glycerol (DOG), which stimulate protein kinase C (PKC), can also increase sperm binding to the zona pellucida and/or enhance induction of the acrosome reaction of bound sperm. Cynomolgus macaque sperm were centrifuged through 60% Percoll and then were washed with modified Biggers, Whitten and Whittingham (BWW) medium and incubated for 2.5 h at 37 degrees C with 5% CO2, ACT, PMA, or DOG was added to sperm during the last 15-30 min of incubation. Sperm were evaluated immediately after incubation for motility and acrosomal status. Macaque oocytes were coincubated with stimulated sperm suspensions in BWW medium for 30 sec (pulse). Half of the oocytes were removed to sperm-free medium and further incubated for 1 h (chase). When assessed after the pulse period, sperm-zona binding increased significantly after ACT treatment compared to that in untreated controls. DOG but not PMA treatment had a similar effect on sperm binding PMA, DOG, and ACT treatment increased the percentage of acrosome reactions in sperm bound to the zona following the 30-sec pulse compared to the percentage in controls. Inactive analogs of PMA and DOG had no effect on sperm-zona binding or the percentage of acrosome reactions (% AR) of bound sperm.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of protein kinase C stimulators on zona pellucida binding and the acrosome reaction of macaque sperm. 763 50

It has been shown that chronic lung diseases which increase the concentration of pulmonary carbon dioxide (CO2) at the expense of oxygen stimulate the secretion of biogenic amines and neuropeptides by pulmonary neuroendocrine cells (PNE cells) in man and laboratory animals. This increase in secretory activity is always accompanied by hyperplasia of PNE cells, and smokers with chronic obstructive lung disease are at high risk for the development of neuroendocrine lung cancer. We have previously shown that nicotine and the structurally related nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), stimulate the proliferation of neuroendocrine cell lines derived from lung carcinoid tumors via interaction with nicotinic acetylcholine receptors (nAChR). In our current experiment, we have addressed the mechanisms of cell proliferation in response to nicotine and NNK in normal PNE cells derived from fetal hamster lungs, and two cell lines derived from human neuroendocrine lung cancers. Our data show that in these systems the mitogenic effects of nicotine and NNK are potentiated in a concentration-dependent manner by elevated levels of CO2, an effect blocked by inhibitors of protein kinase C(PKC) and reduced by antagonists of receptors for 5-hydroxytryptamine (5-HT, serotonin) and mammalian bombesin. The observed effects of CO2 were saturable and independent of changes in the acidity of the tissue culture media. Our data suggest that increases in CO2 concentration at the expense of oxygen may stimulate signal transduction pathways in normal and neoplastic neuroendocrine lung cells thus enhancing their susceptibility to the mitogenic effects of tobacco-specific toxicants.
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PMID:Carbon dioxide potentiates the mitogenic effects of nicotine and its carcinogenic derivative, NNK, in normal and neoplastic neuroendocrine lung cells via stimulation of autocrine and protein kinase C-dependent mitogenic pathways. 771 58

The roles of protein kinase C (PKC) in regulation of the plasmalemmal vacuolar-type H(+)-ATPase (V-ATPase) and Na(+)-H+ exchanger (NHE) of rabbit alveolar macrophages (m phi) were investigated using phorbol 12-myristate 13-acetate (PMA). At an extracellular pH (pHo) of 7.4 (nominal absence of CO2-HCO3-), PMA caused a dose-dependent increase in the rate of cellular H+ extrusion with little change in intracellular pH (pHi). PMA caused a prolonged cytosolic acidification at pHo < or = 6.8. PMA-induced changes in pHi were sensitive to bafilomycin A1, but were insensitive to amiloride. Studies of pHi recovery following intracellular acid challenge showed that both V-ATPase and the NHE were up-regulated by PMA. An inactive analog, 4 alpha-phorbol, had no detectable effects on pHi homeostasis. These data indicate that (a) PKC is involved in regulation of V-ATPase and the NHE of resident alveolar m phi and (b) V-ATPase is the predominant mechanism for pHi homeostasis in unstimulated and PMA-activated m phi.
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PMID:Effects of myristate phorbol ester on V-ATPase activity and Na(+)-H+ exchange in alveolar macrophages. 772 18

The aim of these experiments was to study acute regulation of proximal tubule H+/HCO3- transport systems in acid-base disorders. Proximal tubular suspensions were prepared from rabbit kidney cortex and incubated in acidic (pH 6.9), control (pH 7.4), or alkalotic (pH 8.0) media for 45 minutes and gassed with 5% CO2. Brush border membrane (BBM) and basolateral membrane (BLM) vesicles were isolated from the tubular suspensions and studied for the activity of the pH-regulating transport systems. Influx of amiloride-sensitive 22Na at 10 seconds (pHo 7.5, pHi 6.0) into BBM vesicles was 36% higher in the acidotic and 51% lower in alkalotic groups compared to control. HCO3-dependent 22Na uptake was increased by 55% in BLM vesicles from acidotic and remained unchanged in ones from alkalotic tubules. The presence of 250 nmol/L staurosporine during incubation in acidic medium reduced the activities of Na+/H+ exchange and Na+/HCO3- cotransport by 19% and 17%, respectively. 36Chloride influx into BBM vesicles (mediated via Cl-/Cl- exchange) remained unchanged in vesicles harvested from tubules in acidic and alkalotic media. However, 36chloride influx into BLM vesicles (mediated via Cl-/Cl- exchange) decreased by 23% in the acidic and increased by 37% in the alkalotic group. Staurosporine had no effect on Cl/base exchange in BLM vesicles isolated from control, acidotic, or alkalotic tubules. We conclude that in vitro acid-base disorders are associated with complex and preferential adaptive changes in certain pH-regulating processes in kidney proximal tubules. Some of these effects are partially mediated via protein kinase C.
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PMID:Acute regulation of Na+/H+ exchange, Na+:HCO3- cotransport, and C1-/base exchange in acid base disorders. 803 6


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