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)

Cultured ovine oligodendrocytes (OLGs) express a number of voltage-dependent potassium currents after they attach to a substratum and as they begin to develop processes. At 24-48 hours following plating, an outward potassium current can be identified that represents a composite response of a rapidly inactivating component and a steady-state or noninactivating component. After 4-7 days in culture, OLGs also develop an inward rectifier current. We studied the effects of forskolin and phorbol 12-myristate 13-acetate (PMA) on OLG outward currents. These compounds are known to alter the myelinogenic metabolism of OLGs. PMA, an activator of protein kinase C (PK-C), has been shown to enhance myelin basic protein phosphorylation while forskolin acting on adenylate cyclase, and thereby increasing cAMP, inhibits it. Both forskolin and PMA increase the phosphorylation of 2'3'-cyclic nucleotide phosphodiesterase, an OLG/myelin protein. We found that forskolin decreased the steady-state outward current at 120 mV by 10% at 100 nM, and by 72% at 25 microM from a holding potential of -80 mV. The time course of inactivation of the peak currents was decreased, affecting both the fast and slow time constants. There was no significant change in the steady-state parameters of current activation and inactivation. The effect of forskolin was attenuated when the adenylate cyclase inhibitor adenosine (2 mM) was present in the intracellular/pipette filling solution. The results of PMA experiments were similar to those obtained with forskolin. Whereas the amplitude of the currents in the presence of PMA was reduced by 28% at 1.5 nM and 60% and 600 nM, the decay phase of the peak currents was less affected. The PMA effect could still be seen when the intracellular Ca2+ was reduced to less than or equal to 10 nM with 5 mM BAPTA, but was inhibited when the cells were pre-exposed to 50 microM psychosine, a PK-C inhibitor. It is postulated that the potassium currents in OLG can be physiologically modulated by two distinct second-messenger systems, perhaps converging at the level of a common phosphorylated enzyme or regulatory protein.
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PMID:Forskolin and phorbol esters decrease the same K+ conductance in cultured oligodendrocytes. 321 67

K-259-2, a new inhibitor of Ca2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase, was isolated from the cultured broth of Micromonospora olivasterospora K-259. K-259-2 has an anthraquinone moiety in its structure. IC50 values for the effect of K-259-2 against Ca2+ and calmodulin-stimulated activity of the enzyme preparations from bovine brain and heart were 6.6 and 2.9 microM, respectively. On the other hand, basal activity (the activity in the presence of ethylene bis(oxyethylenenitrilo)tetraacetic acid (EGTA) instead of Ca2+/calmodulin) of the bovine brain enzyme, calmodulin-independent cyclic nucleotide phosphodiesterase from bovine heart, and protein kinase C from rat brain were inhibited by K-259-2 to a lesser extent with IC50 values of 27.4, 40.7 and 45.8 microM, respectively.
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PMID:K-259-2, a new inhibitor of Ca2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase from Micromonospora olivasterospora. 368 20

KS-619-1, a new inhibitor of Ca2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase, was isolated from the cultured broth of Streptomyces californicus. KS-619-1 has an anthraquinone moiety. IC50 values for the effect of KS-619-1 on Ca2+ and calmodulin-stimulated activity of bovine brain and heart enzymes were 2.0 and 1.5 microM, respectively. On the other hand, basal activity (the activity in the presence of ethylene bis(oxyethylenenitrilo)tetraacetic acid (EGTA) instead of Ca2+/calmodulin) of the bovine brain enzyme, calmodulin-independent cyclic nucleotide phosphodiesterase from bovine heart, and protein kinase C from rat brain were inhibited by KS-619-1 to a lesser extent with IC50 values; 12.3, 25.9 and 151 microM, respectively.
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PMID:KS-619-1, a new inhibitor of Ca2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase from Streptomyces californicus. 368 22

We have previously described the use of Ca2+-dependent hydrophobic-interaction chromatography to isolate the Ca2+ + phospholipid-dependent protein kinase (protein kinase C) and a novel heat-stable 21 000-Mr Ca2+-binding protein from bovine brain [Walsh, Valentine, Ngai, Carruthers & Hollenberg (1984) Biochem. J. 224, 117-127]. The procedure described for purification of the 21 000-Mr calciprotein to electrophoretic homogeneity has been modified to permit the large-scale isolation of this Ca2+-binding protein, enabling further structural and functional characterization. The 21 000-Mr calciprotein was shown by equilibrium dialysis to bind approx. 1 mol of Ca2+/mol, with apparent Kd approx. 1 microM. The modified large-scale purification procedure revealed three additional, previously unidentified, Ca2+-binding proteins of Mr 17 000, 18 400 and 26 000. The 17 000-Mr and 18 400-Mr Ca2+-binding proteins are heat-stable, whereas the 26 000-Mr Ca2+-binding protein is heat-labile. Use of the transblot/45CaCl2 overlay technique [Maruyama, Mikawa & Ebashi (1984) J. Biochem. (Tokyo) 95, 511-519] suggests that the 18 400-Mr and 21 000-Mr Ca2+-binding proteins are high-affinity Ca2+-binding proteins, whereas the 17 000-Mr Ca2+-binding protein has a relatively low affinity for Ca2+. Consistent with this observation, the 18 400-Mr and 21 000-Mr Ca2+-binding proteins exhibit a Ca2+-dependent mobility shift on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, whereas the 17 000-Mr Ca2+-binding protein does not. The amino acid compositions of the 17 000-Mr, 18 400-Mr and 21 000-Mr Ca2+-binding proteins show some similarities to each other and to calmodulin and other members of the calmodulin superfamily; however, they are clearly distinct and novel calciproteins. In functional terms, none of the 17 000-Mr, 18 400-Mr or 21 000-Mr Ca2+-binding proteins activates either cyclic nucleotide phosphodiesterase or myosin light-chain kinase, both calmodulin-activated enzymes. However, the 17 000-Mr Ca2+-binding protein is a potent inhibitor of protein kinase C. It may therefore serve to regulate the activity of this important enzyme at elevated cytosolic Ca2+ concentrations.
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PMID:Ca2+-binding proteins from bovine brain including a potent inhibitor of protein kinase C. 409 8

Several bovine brain proteins have been found to interact with a hydrophobic chromatography resin (phenyl-Sepharose CL-4B) in a Ca2+-dependent manner. These include calmodulin, the Ca2+/phospholipid-dependent protein kinase (protein kinase C) and a novel Ca2+-binding protein that has now been purified to electrophoretic homogeneity. This latter protein is acidic (pI 5.1) and, like calmodulin and some other high-affinity Ca2+-binding proteins, exhibits a Ca2+-dependent mobility shift on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, with an apparent Mr of 22 000 in the absence of Ca2+ and Mr 21 000 in the presence of Ca2+. This novel calciprotein is distinct from known Ca2+-binding proteins on the basis of Mr under denaturing conditions, Cleveland peptide mapping and amino acid composition analysis. It may be a member of the calmodulin superfamily of Ca2+-binding proteins. This calciprotein does not activate two calmodulin-dependent enzymes, namely cyclic nucleotide phosphodiesterase and myosin light-chain kinase, nor does it have any effect on protein kinase C. It may be a Ca2+-dependent regulatory protein of an as-yet-undefined enzymic activity. The Ca2+/phospholipid-dependent protein kinase is also readily purified by Ca2+-dependent hydrophobic-interaction chromatography followed by ion-exchange chromatography, during which it is easily separated from calmodulin. A preparation of protein kinase C that lacks contaminating kinase or phosphatase activities is thereby obtained rapidly and simply. Such a preparation is ideal for the study of phosphorylation reactions catalysed in vitro by protein kinase C.
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PMID:Ca2+-dependent hydrophobic-interaction chromatography. Isolation of a novel Ca2+-binding protein and protein kinase C from bovine brain. 609 14

MS-282a and MS-282b were isolated from the culture broth of Streptomyces tauricus ATCC 27470 as inhibitors of smooth muscle myosin light chain kinase (MLCK). MS-282a and MS-282b inhibited the activity of chicken gizzard MLCK with IC50 values of 3.8 microM and 5.2 microM, respectively. Cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase and protein kinase C were not inhibited by 150 microM MS-282a at all. It is likely that MS-282a blocks MLCK activity by antagonizing calmodulin since 1) the compound inhibited calmodulin-dependent but not calmodulin-independent activity of MLCK; 2) the inhibition of MLCK was antagonized by increasing concentrations of calmodulin, and 3) the compound inhibited calmodulin-dependent cyclic nucleotide phosphodiesterase.
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PMID:MS-282a and MS-282b, new inhibitors of calmodulin-activated myosin light chain kinase from Streptomyces tauricus ATCC 27470. 792 70

Smooth muscle calponin bound to the biologically active fluorescent calmodulin [2-(4'-maleimidoanilino)naphthalene-6-sulfonic acid-calmodulin] (MIANS.CaM) with a Kd of 80 nM and produced a 3.4-fold fluorescence enhancement. PKC-phosphorylated calponin (1.3 mol of Pi/mol) bound to CaM with approximately 15-fold lower affinity. Calponin inhibited CaM (10 nM) activation of the Ca(2+)-/CaM-activated cyclic nucleotide phosphodiesterase (PDE) with an IC50 of 138 nM. The calponin-CaM interaction was Ca(2+)-dependent: half-maximal binding of calponin to MIANS.CaM occurred at pCa 6.6 with a Hill coefficient of 2.4. Stopped-flow fluorescence kinetic analysis demonstrated that EGTA chelation of Ca2+ from CaM disrupted the MIANS.CaM-calponin complex at a rate of 1 s-1. Calponin bound MIANS.CaM at a rate of (6.0 +/- 1.8) x 10(6) M-1s-1, and melittin and unlabeled brain CaM both disrupted the MIANS.CaM-calponin complex at a rate of 0.3 +/- 0.1 s-1. These studies suggest that calponin binds CaM with 80-fold lower affinity than myosin light-chain kinase and that calponin associates with CaM much slower than it associates with caldesmon or myosin light-chain kinase. The physiological relevance of the CaM-calponin interaction was evaluated by analysis of the effects of Ca(2+)-CaM on (i) the interaction of calponin with actin and (ii) calponin-mediated inhibition of actin-activated myosin MgATPase activity. Ca(2+)-CaM half-maximally inhibited calponin (2 microM) binding to smooth and skeletal muscle actins (9 microM) at 5.4 and 11 microM CaM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calponin-calmodulin interaction: properties and effects on smooth and skeletal muscle actin binding and actomyosin ATPases. 824 Nov 89

Angiotensin II has been shown to act prejunctionally to facilitate sympathetic neutrotransmission in various tissues including the iris-ciliary body. In the present study, we characterized the prejunctional angiotensin II receptor subtype and its signal transduction pathway in the rabbit iris-ciliary body. Angiotensin II caused concentration-dependent facilitation of electrically evoked [3H]-norepinephrine overflow from the isolated, superfused rabbit iris-ciliary body without affecting basal tritium efflux. Responses to angiotensin II were antagonized by saralasin and DuP753 but not by PD123177 indicating that prejunctional angiotensin II receptors of the AT1-subtype mediate the facilitation of evoked [3H]-norepinephrine release. The non-selective cyclic nucleotide phosphodiesterase inhibitor, isobutylmethyl xanthine enhanced the angiotensin II response whereas the cAMP-specific phosphodiesterase inhibitor, RO-20-1724 had no effect. In the presence of 8-bromo-cGMP, responses elicited by angiotensin II were significantly (P < 0.01) greater than that caused in the absence of 8-bromo-cGMP. In contrast, 8-bromo-cAMP had no effect on the angiotensin II-induced response. Guanylate cyclase inhibitors, methylene blue and LY83583 abolished angiotensin II-induced enhancement of [3H]-norepinephrine overflow without affecting basal tritium efflux. Taken together, these results suggest that cGMP could be involved in the angiotensin II response. Neither phospholipase C inhibitors (neomycin, 2-nitro-4-carboxyphenyl-N,N-diphenyl carbamate and phenylmethylsulfonyl fluoride) nor an inhibitor of protein kinase C (staurosporine) had any significant effect on the angiotensin II response, indicating that metabolites of inositol phospholipid metabolism or activation of protein kinase C are not involved in the response to this peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prejunctional receptors and second messengers for angiotensin II in the rabbit iris-ciliary body. 828 27

MS-347a was isolated from the culture broths of Aspergillus sp. KY52178 as an inhibitor of smooth muscle myosin light chain kinase (MLCK). MS-347a inhibited the activity of chicken gizzard MLCK with an IC50 value of 9.2 microM. The inhibition was dependent on time of preincubation of MS-347a with the enzyme, suggesting irreversible inhibition. It is likely that the inhibitor binds to the catalytic domain of MLCK, since the compound inhibited not only calmodulin-dependent but also calmodulin-independent activity of MLCK. Calmodulin-dependent cyclic nucleotide phosphodiesterase, cAMP-dependent protein kinase and cGMP-dependent protein kinase were not inhibited by 150 microM MS-347a at all, although the compound inhibited protein kinase C with an IC50 value of 16 microM. MS-347b, a minor component was also isolated from the same culture broths. This minor component at 150 microM did not inhibit the activity of MLCK.
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PMID:MS-347a, a new inhibitor of myosin light chain kinase from Aspergillus sp. KY52178. 829 33

Primary and first-passage dog urothelial cells (DUC and DUC-P1, respectively) exhibited an active catalytic subunit for the cyclic adenosine monophosphate (cAMP) second messenger system. Dramatic increases in cAMP levels were observed following the addition of forskolin, which elicited a time- and dose-response--dependent increase in cAMP levels. Increases in intracellular cAMP levels preceded media increases in cyclic nucleotide levels and were observed at the earliest time examined (5 minutes). The lowest effective concentration of forskolin was between 1 and 10 mumol/L. cAMP level increases as large as 20- to 100-fold were observed in cells and media. Preincubation of primary and subcultured cells with 0.1 mumol/L 12-O-tetradecanoylphorbol-13-acetate (TPA) for 60 minutes reduced the magnitude of the forskolin-induced increase in cAMP levels. To determine the mechanism by which TPA elicits its effect in primary cultures, the following test agents were used: 1.0 mumol/L staurosporine and 25 mumol/L sphingosine, protein kinase C inhibitors; 35 mumol/L cycloheximide, a protein synthesis inhibitor; 3.0 mumol/L indomethacin, an inhibitor of prostaglandin synthesis; and 0.5 mmol/L RO-20-1724, a cyclic nucleotide phosphodiesterase inhibitor. Staurosporine and sphingosine were the only agents that prevented the effect of TPA. The specificity of the TPA effect was evaluated with the following test agents: 0.2 nmol/L epidermal growth factor (EGF), 0.1 mumol/L 4 alpha-TPA (a stereoisomer of TPA), or 1.0 mumol/L A23187. In contrast to TPA, none of these agents reduced forskolin-mediated increases in cAMP. Results indicate forskolin cAMP responsiveness and regulation of this response by TPA in both primary and subcultured cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic adenosine monophosphate response in primary and subcultured bladder epithelial cells: inhibition by 12-O-tetradecanoylphorbol-13-acetate. 838 23


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