EC:2.7.11.13 - FACTA Search

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

Earlier studies established that adenylyl cyclase in NCB-20 cell plasma membranes is inhibited by concentrations of Ca2+ that are achieved in intact cells. The present studies were undertaken to prove that agents such as bradykinin and ATP, which elevate the cytosolic Ca2+ concentration ([Ca2+]i) from internal stores in NCB-20 cells, could inhibit cyclic AMP (cAMP) accumulation as a result of their mobilization of [Ca2+]i and not by other mechanisms. Both bradykinin and ATP transiently inhibited [3H]cAMP accumulation in parallel with their transient mobilization of [Ca2+]i. The [Ca2+]i rise stimulated by bradykinin could be blocked by treatment with thapsigargin; this thapsigargin treatment precluded the inhibition of cAMP accumulation mediated by bradykinin (and ATP). A rapid rise in [Ca2+]i, as elicited by bradykinin, rather than the slow rise evoked by thapsigargin was required for inhibition of [3H]cAMP accumulation. Desensitization of protein kinase C did not modify the inhibitory action of bradykinin on [3H]cAMP. Effects of Ca2+ on phosphodiesterase were also excluded in the present studies. The accumulated data are consistent with the hypothesis that hormonal mobilization of [Ca2+]i leads directly to the inhibition of cAMP accumulation in these cells and presumably in other cells that express the Ca(2+)-inhibitable form of adenylyl cyclase.
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PMID:Inhibition of cyclic AMP accumulation in intact NCB-20 cells as a direct result of elevation of cytosolic Ca2+. 132 28

We have examined the activation of a phospholipase C signal transduction pathway by a B2-bradykinin receptor in the human astrocytoma cell line D384 and how this influences D1-dopamine receptor stimulated cyclic AMP accumulation. Addition of bradykinin to D384 cells resulted in a concentration-dependent (10(-11)-10(-6) M) increase in the accumulation of [3H]inositol phosphates and a similar concentration-dependent transient increase in specific [3H]beta-phorbol-12,13-dibutyrate binding which is indicative of translocation of protein kinase C from the cytosol to the membrane. Changes in intracellular Ca2+ of single cells, measured using the fluorescent indicator dye fura-2, indicated that bradykinin produced a rapid, but transient, increase in intracellular calcium. The Ca2+ response was largely independent of extracellular Ca2+ supporting the idea that receptor activation leads to mobilization of Ca2+ from intracellular stores. However, extracellular Ca2+ was required for a response to a rechallenge with bradykinin. The bradykinin B2-receptor agonist kallidin increased cytosolic Ca2+ in a similar manner to bradykinin. The Ca2+ response to bradykinin could be partially reduced in the presence of the B2-receptor antagonist [D-Arg0-Hyp,D-Phe7,beta-(2-Thienyl)-Ala5,8]-bradykinin, whereas the B1-receptor agonists (Des-Arg9]-bradykinin and [Des-Arg10]-kallidin were ineffective. Bradykinin was also found to attenuate dopamine stimulated cyclic AMP accumulation in D384 cells, at similar concentrations previously observed to stimulate the phospholipase C signal transduction pathway, in the presence of the phosphodiesterase inhibitor, rolipram. In contrast, no attenuation was observed in the presence of the phosphodiesterase inhibitor 1-isobutyl 3-methylxanthine, although the level of dopamine stimulated cyclic AMP observed was lower than in the presence of rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a B2-bradykinin receptor linked to phospholipase C and inhibition of dopamine stimulated cyclic AMP accumulation in the human astrocytoma cell line D384. 132 96

This review considers the hypothesis that the endothelium-derived vasodilator agents, prostacyclin and nitric oxide, also function physiologically to inhibit vascular smooth muscle cell (VSMC) proliferation. The underlying biochemical mechanisms are also discussed. Prostacyclin and other agents that increase intracellular cAMP concentration are potent and effective inhibitors of the proliferation of isolated VSMC in culture. Such agents inhibit the initiation of proliferation in quiescent cells and the proliferation of logarithmically growing cells from a variety of sources, including man. The data implicate prostacyclin as an important regulator of VSMC proliferation, although there is little direct in vivo evidence. Nitric oxide-releasing drugs (and atriopeptins which increase intracellular cGMP concentration by a different mechanism) also inhibit proliferation of cultured VSMC. The effects are, however, partial and obtained at higher concentrations than those required for vasodilatation. Even allowing for the instability of the agents under tissue culture conditions, cGMP-elevating agents appear to be poorer at inhibiting proliferation than cAMP-elevating agents, despite similar or greater vasodilator potency. These data imply that nitric oxide is less likely than prostacyclin to be a physiological regulator of VSMC proliferation, although definitive experiments in vivo are again lacking. It also follows that nitrovasodilators are less attractive as therapy for VSMC proliferation than prostacyclin analogues or other cAMP-elevating agents, such as phosphodiesterase inhibitors. By analogy with the mechanisms of vasodilatation, inhibition of calcium mobilization and the subsequent activation of protein kinase C are considered as possible mechanisms underlying inhibition of proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of vascular smooth muscle cell proliferation by endothelium-dependent vasodilators. 133 37

We investigated the mechanism by which alpha 1-adrenergic activation regulates basal and stimulated whole cell L-type Ca current (ICa) in rat ventricular myocytes using the physiological neurotransmitter, norepinephrine (NE, 10 microM). Stimulation of alpha 1-adrenoceptors, achieved by NE + 10 microM esmolol (a beta-receptor antagonist), had no significant effect on basal ICa. alpha 1-adrenergic activation had a marked inhibitory effect on ICa elevated by beta activation (NE + 1 microM) prazosin, an alpha 1-receptor antagonist) or activation of adenylyl cyclase by forskolin (25 microM); the inhibitory effect was reversible upon washout. However, alpha 1-adrenergic stimulation had no significant effect on ICa previously increased by intracellular application of cAMP (25 microM). The inhibitory effect seen on ICa elevated by NE showed no significant shift of either I-V or inactivation curves. It is unlikely that the inhibitory effect of alpha 1-adrenergic stimulation on NE or forskolin-elevated ICa is mediated through activation of Ca-dependent protein kinase C or changes in intracellular free Ca (pCa = 8.5, EGTA 5 mM) or cAMP-dependent phosphodiesterase. We conclude that alpha 1-adrenergic inhibition of beta-adrenergic stimulated-ICa is probably mediated through an as yet unknown G-protein. This inhibitory effect could serve as a regulatory feedback mechanism in physiological and pathophysiological settings.
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PMID:Alpha 1- and beta-adrenergic interactions on L-type calcium current in cardiac myocytes. 135 26

1. The potassium currents evoked by glutamate agonists on isolated and identified neurones of molluscan pedal ganglia were investigated using the voltage clamp technique. 2. Glutamate responses were not modified by increasing intracellular cyclic nucleotide concentrations (treatment with 8-Br-cAMP, 8-Br-cGMP, forskolin and/or the phosphodiesterase inhibitor isobutylmethylxantine, IBMX), whereas inward-going currents induced by the nucleotides were observed. It follows that glutamate currents are independent of intracellular cyclic nucleotide control. 3. Protein kinase C activation with phorbol esters or oleoylacetylglycerol induced a slowly developing outward current and reduced glutamate response amplitude. Staurosporine itself did not affect the glutamate responses but completely prevented the effects of phorbol esters and oleoylacetylglycerol. This indicated that protein kinase C was not involved in the transduction mechanism for the potassium component of the glutamate response. 4. The possible involvement of inositol-1,4,5-trisphosphate seems to be improbable because the glutamate responses were independent of intracellular calcium concentration. Intracellular injection of calcium buffer BAPTA, failed to affect any of the glutamate currents, although it effectively blocked the after-hyperpolarization following directly evoked action potentials. 5. Nordihydroguaiaretic acid (NDGA) and indomethacin, inhibitors of the lipoxygenase and cyclo-oxygenase pathways of arachidonic acid metabolism, correspondingly, did not change the glutamate responses of these neurones. 6. The failure to demonstrate the involvement of any known secondary messenger systems in glutamate response transduction favours two assumptions: (1) the receptor-G protein complex controls the potassium channel directly; or (2) some still unknown transduction system is used.
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PMID:Transduction mechanism for glutamate-induced potassium current in neurones of the mollusc Planorbarius corneus. 136 43

A novel compound, KS-505a was isolated from the culture broth of a strain identified as Streptomyces argenteolus A-2. The compound inhibited bovine brain Ca2+ and calmodulin-dependent cyclic-nucleotide phosphodiesterase with an IC50 value (the concentration causing 50% inhibition) of 0.065 microM. The compound around that concentration had little or no effect on heart calmodulin-dependent and -independent cyclic-nucleotide phosphodiesterases, and protein kinase C.
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PMID:KS-505a, a novel inhibitor of bovine brain Ca2+ and calmodulin-dependent cyclic-nucleotide phosphodiesterase from Streptomyces argenteolus. 137 73

Nitric oxide (NO) is an important molecular messenger accounting for endothelial-derived relaxing activity in blood vessels, mediating cytotoxic actions of macrophages, and functioning as a neurotransmitter in the brain and periphery. NO synthase (NOS) from brain has been purified to homogeneity and molecularly cloned. We now report that NOS is stoichiometrically phosphorylated by cAMP dependent protein kinase, protein kinase C, and calcium/calmodulin-dependent protein kinase, with each kinase phosphorylating a different serine site on NOS. Activation of PKC in transfected cells reduces NOS enzyme activity by approximately 77% in intact cells and by 50% in protein homogenates from these cells. Utilizing fluorescence spectroscopy we find that purified monomer NOS contains 1 molar equivalent of both FMN and FAD. This stoichiometry is supported by enzymatic digestion of the flavins with phosphodiesterase, and titration of the FMN with a specific FMN binding protein. We demonstrate that purified NOS is labeled by a photoaffinity derivative of calmodulin. These recognition sites on NOS provide multiple means for regulation of NO levels and "cross-talk" between second messenger systems.
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PMID:Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. 137 33

Previous studies suggested that the transition from an incompetent to a competent meiotic state during the course of oogenesis in the mouse involved a G2/M-like cell cycle transition (Wickramasinghe et al, 1991. Dev. Biol. 143, 162). The present studies tested the hypothesis that centrosome phosphorylation, an event normally induced by MPF, is required for this developmental transition and the expression of meiotic competence in cultured growing mouse oocytes. Multiple fluorescence labeling techniques were used to evaluate centrosome number, phosphorylation status, and microtubule nucleating capacity in competent and incompetent oocytes. Experimental conditions were established for reversibly altering the phosphorylation status of the centrosomes and the effects of these treatments on meiotic resumption were examined. Phosphorylated centrosomes nucleating short microtubules were observed in competent oocytes, whereas nonphosphorylated centrosomes and interphase microtubule arrays were found in incompetent oocytes. Upon recovery from nocodazole-induced microtubule depolymerization, short microtubules formed from centrosomes in competent oocytes, whereas long microtubules reappear in the cytoplasm of incompetent oocytes. Perturbation of the phosphorylation state of oocytes with activators of protein kinase A or protein kinase C resulted in the formation of long interphase microtubules in competent oocytes while centrosome phosphorylation was maintained. Treatment of competent oocytes with the phosphorylation inhibitor 6-dimethylaminopurine also led to formation of long microtubules, although under these conditions centrosomes were dephosphorylated. When competent oocytes were treated simultaneously with puromycin and the phosphodiesterase inhibitor isobutyl methylxanthine (IBMX) for 6 hr, centrosomes became dephosphorylated; centrosomes were rephosphorylated when competent oocytes were further cultured in IBMX without puromycin. Conditions that induced centrosome dephosphorylation in competent oocytes resulted in the loss of the ability to express meiotic competence in culture, whereas maintenance of centrosome phosphorylation in these oocytes was correlated with the ability to resume meiosis. These results suggest that the G2/M transition that occurs when mouse oocytes progress from an incompetent to a competent state in vivo involves the phosphorylation of centrosomes and that the maintenance of centrosome phosphorylation is required for the in vitro expression of meiotic competence.
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PMID:Centrosome phosphorylation and the developmental expression of meiotic competence in mouse oocytes. 137 14

We have examined the regulation of expression of 80K/MARCKS, a major and specific protein kinase C (PKC) substrate of Swiss 3T3 fibroblasts. Addition of bombesin (10 nM) to confluent quiescent cultures of these cells induced a dramatic and sustained down-regulation of 80-kDa mRNA and protein levels to a minimum of 5% of control within 8 and 48 h, respectively, without depletion of PKC activity. In contrast, the effect of phorbol 12,13-dibutyrate on 80K/MARCKS mRNA levels was transient, and recovery of these transcripts correlated with the loss of PKC activity. The ability of bombesin to down-regulate 80K/MARCKS mRNA levels was dose-dependent (ED50 0.5 nM) and was abolished by both the specific bombesin antagonist [Leu13 psi (CH2NH),Leu14]bombesin and by prior depletion of PKC. Of a range of agents tested, platelet-derived growth factor (PDGF), but not insulin or Ca2+ ionophore, also down-regulated 80K/MARCKS mRNA to 24% of control within 5 h. Prior down-regulation of PKC abolished the effect of PDGF at a concentration of 7 ng/ml. Surprisingly, at higher doses (25 ng/ml), PDGF induced the down-regulation of 80K/MARCKS mRNA in a PKC-independent manner. Furthermore, elevation of cAMP, either through receptor-mediated mechanisms (e.g. prostaglandin E1) or by direct stimulation of adenylate cyclase (e.g. forskolin), also caused a marked dose-dependent depletion of 80K/MARCKS mRNA levels, which were further reduced by co-administration with cAMP-phosphodiesterase inhibitors. The rate of transcription of the 80K/MARCKS gene was unaltered by treatment of cells with either bombesin, PDGF, or forskolin/1-methyl-3-isobutylxanthine. These results indicate a role for both PKC-dependent and -independent pathways in growth factor-induced down-regulation of 80K/MARCKS expression, through a post-transcriptional mechanism.
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PMID:The expression of 80K/MARCKS, a major substrate of protein kinase C (PKC), is down-regulated through both PKC-dependent and -independent pathways. Effects of bombesin, platelet-derived growth factor, and cAMP. 137 35

Exposure of C62B rat glioma cells to fresh medium containing fetal bovine serum induced a sensitization of the subsequent ability of isoproterenol and forskolin to stimulate cyclic AMP accumulation, compared to cells exposed to fresh medium without serum. Isoproterenol stimulation was typically increased by 2- to 4-fold and forskolin stimulation by 3- to 5-fold. Sensitization occurred rapidly, was rapidly reversible and appeared to result from an increase in maximal stimulation. A commercial preparation of albumin, purified chromatographically so as to retain bound lipids and other factors, was able to mimic the effect of serum. In contrast to the effects of serum, exposure of cells to phorbol 12-myristate, 13-acetate induced little or no change in forskolin stimulation but a marked desensitization of isoproterenol stimulation that was due primarily to a decrease in potency. Neither the protein kinase C inhibitor staurosporine or overnight exposure to phorbol 12-myristate, 13-acetate to down-regulate protein kinase C prevented serum-induced sensitization. Pertussis toxin almost completely blocked serum-induced sensitization, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in mediating the effects of serum. Sensitization was poorly retained in membrane adenylate cyclase assays. Studies with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, direct assays of cyclic AMP degradation by intact cells and assays of phosphodiesterase activity in cell lysates all indicated that degradation of cyclic AMP was decreased in serum-pretreated cells. Thus, both increased cyclic AMP synthesis and decreased cyclic AMP degradation may contribute to sensitization in these cells.
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PMID:Serum-induced sensitization of cyclic AMP accumulation in C62B rat glioma cells. 138 77

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