Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The response of the Na efflux in unpoisoned barnacle fibers to 10 mM theophylline is biphasic; i.e., inhibition is followed by stimulation. The stimulatory response is unaffected by ouabain. Fibers pretreated with ouabain show no transitory inhibition when 10 mM theophylline is applied, but show prompt stimulation the magnitude of which is comparable to that observed with unpoisoned fibers. The same holds true for lower concentrations of theophylline. Prior injection of 500 mM EGTA completely abolishes the biphasic action of 10 mM theophylline. External application of 10 mM theophylline following removal of external Ca2+ fails to bring about a biphasic effect. Ca2+ restoration, however, results in a moderate rise in the Na efflux. External application of 10 mM theophylline stimulates the Na efflux into Ca2+-free artificial seawater (ASW) when the test fibers are pretreated with ouabain. Injection of the protein inhibitor of Walsh leads to reduced stimulation by 10 mM theophylline of the Na efflux in unpoisoned fibers. Injection of the protein inhibitor of Corbin into unpoisoned fibers leads to reduced stimulation by 10 mM theophylline. Injection of cAMP into ouabain-poisoned fibers, following internal application of Corbin's inhibitor and external application of 10 mM theophylline, fails to cause a marked rise in the ouabain-insensitive Na efflux. Injection of Corbin's inhibitor into ouabain-poisoned fibers, following the onset of peak stimulation by 10 mM theophylline, fails to reduce the Na efflux. Fibers injected with 1 mM and 100 mM EGTA and exposed to 10 mM theophylline show a marked reduction in the response of the ouabain-insensitive Na efflux to injected cAMP when the concentration of theophylline is 10 mM. A poor response to injected cAMP is also seen in fibers bathed in Ca-free ASW containing 10 mM theophylline. Theophylline (10 mM) fails to cause an enhanced stimulation of the ouabain-insensitive Na efflux into Ca-free 3 mM-HEPES ASW or 10 mM-Ca2+ -3mM-HEPES ASW following the addition of protons to the bathing medium. An enhanced response is similarly not observed with injected cAMP following the addition of theophylline to the bathing medium. Injection of 8-fluorotheophylline, 3-isobutyl-1-methylxanthine and doxantrazole leads to a marked reduction in the response of the ouabain-insensitive Na efflux to injected cAMP. Contraction always takes place upon injecting these substances. These results are in keeping with the theory that theophylline acts chiefly by reducing myoplasmic pCa(pCa=-log10[Ca2+]), and that a reduced pCa leads to stimulation of the ouabain-insensitive Na efflux as the result of activation of the cGMP-dependent protein kinase system by newly formed cGMP.
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PMID:Mode of action of theophylline on sodium efflux in barnacle muscle fibers. 20 85

A heat-stable protein which inhibits cAMP dependent protein kinase was prepared from the bovine thyroid 100,000 X g supernatant. This protein inhibited the cAMP-dependent protein kinase both from bovine thyroid cytosol and bovine thyroid plasma membranes. The inhibitory effect was noncompetitive with histone as substrate of the cytosolic enzyme. The stimulatory modulator for cGMP-dependent protein kinase was separated from the 100,000 X g supernatant by Sephadex G-100 gel filtration. The stimulatory modulator had no stimulating effect on cAMP-dependent phosphorylation, and the inhibitory modulator of cAMP-dependent enzyme had no effect on cGMP-requiring phosphorylations. The inhibitory modulator may regulate cAMP-dependent protein kinase activity in cytosol and plasma membrane, and the stimulatory modulator for cGMP-dependent protein kinase may have a role in thyroid function independent of the cAMP-requiring system.
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PMID:Cyclic nucleotide-dependent protein kinase modulators in thyroid tissue. 22 Dec

8-Azidoguanosine 3',5'-cyclic monophosphate (8-N3cGMP) has been synthesized for use as a photoactive probe for the labeling of cGMP receptors. The ability of 8-N3cGMP to be bound at specific cGMP binding sites was demonstrated by its ability to activate cGMP-dependent protein kinase isolated from bovine lung (Ka = 1.1 x 10(-7) M) and to inhibit competitively the binding of [3H] cGMP to the enzyme [Kd (8 N3GMP)/Kd (cGMP) = 6]. Photolysis of 8-N3[32P]cGMP in the presence of a crude enzyme preparation resulted in the covalent attachment of analog to cGMP-dependent protein kinase. Half-maximal labeling occurred at 2.2 x 10(-7) M. The incorporation of the analog was completely inhibited by the addition of cGMP.
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PMID:Synthesis and use of 8-azidoguanosine 3',5'-cyclic monophosphate as photoaffinity label for cyclic GMP-dependent protein kinase. 22 18

The rat cerebellum contains a significant amount of cGMP-dependent protein kinase, cAMP-dependent and cyclic nucleotide-independent protein kinase, and a large concentration of protein kinase inhibitors. These inhibitors are thermostable proteins which can be separated by gel chromatography into two molecular forms: the type 1 and type 2 inhibitors of protein kinase (14). The type 1 inhibitor blocks the rat cerebellar cAMP-dependent protein kinase activity while the type 2 inhibitor blocks the cGMP-dependent protein kinase, the cAMP-dependent protein kinase, and the cyclic nucleotide-independent protein kinases. The activity of the type 2 inhibitor increased or decreased in opposite direction to changes of cerebellar cGMP content generated by injection of 10 mg/kg harmaline 2.5 mg diazepam. No changes of type 1 inhibitor were observed under these conditions. The drug-induced shift of type 2 inhibitor of protein kinase was not mediated by changes in protein synthesis because it persisted after pretreatment with cycloheximide. These results are compatible with the hypothesis that cGMP modulates phosphorylation in cerebellum by changing the relationship between cGMP-dependent protein kinase and type 2 inhibitor content.
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PMID:Action of harmaline and diazepam on the cerebellar content of cyclic GMP and on the activities of two endogenous inhibitors of protein kinase. 22 76

Since the effects of cyclic nucleotides are mediated via protein kinases activation, we have studied the properties and regulation of these enzymes in cytosol and particulate fraction of normal cerebral tissues and of some human brain tumors. We found that distribution and activity of cyclic nucleotide-dependent protein kinases are regulated differently among various brain tumors and in comparison to normal gray and white matter. Pathological tissues show an higher cGMP-dependent protein kinase and this biochemical pattern is particularly evident in tumors with more pronounced malignancy. These data further confirm the hypothesis of a correlation between the increase of cGMP function and cellular growth and malignancy.
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PMID:Basal, cAMP- and cGMP-dependent protein kinases in human brain tumors. 23 64

Synaptosomal membranes prepared from different anatomical regions of postmortem human brain readily incorporate phosphate when incubated with labelled ATP in vitro. Separation of proteins on SDS slab gels indicated up to 30 protein bands stained by Coomassie blue of which ten incorporated label, as detected by radioautography (mol. wt. range 16-110 K with a major double band at 49-50 K). Incorporation into the 110 K region appeared to increase in older persons, and that into the 49-50 K region decreased. Human but not rat membranes subjected to similar conditions of treatment failed to respond to the addition of cAMP at 10(-5) - 10(-7) M but were highly sensitive to the addition of cGMP at 10(-6) M, which led to intensification of existing bands and the appearance of a major band at 60 K. The 110 K band present in high concentration in white matter striatum, caudate nucleus, and putamen was insensitive to cGMP addition. The presence of cGMP-dependent protein kinase substrates has not previously been reported in synapses, and it may be of significance in view of the known sensitivity of this system to biological regulatory agents.
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PMID:Protein phosphorylation in human synaptosomal membranes: evidence for the presence of substrates for cyclic nucleotide guanosine 3'-5'-monophosphate dependent protein kinases. 23 73

Several new 8-alkyl and 8-acyl derivatives of quanosie 3',5'-cyclic phosphate (cGMP) and inosine 3',5'-cyclic phosphate (cGMP) were prepared by direct alkylation or acylation of the parent cyclic nucleotide via free radicals generated in situ. These compounds have been examined for their ability to stimulate a cGMP-dependent protein kinase, and several of the cGMP derivatives were as active in this regard as cGMP. These compounds proved to be quite ineffective when tested for their ability to activate an adenosine 3',5'-cyclic phosphate (cAMP) dependent protein kinase. In addition, these 8-substituted cGMP derivatives are not substrates for a phosphodiesterase preparation from rabbit kidney, but do show inhibition of the hydrolysis of cAMP by crude phosphodiesterase preparations from rabbit lung and beef heart.
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PMID:Synthesis and enzymic activity of 8-acyl and 8-alkyl derivatives of guanosine 3, 5-cyclic phosphate. 23 54

Elevation of either cAMP or cGMP causes smooth muscle relaxation. Whether these effects are mediated through cAMP-dependent protein kinase (cAK), cGMP-dependent protein kinase (cGK), or both is unknown. Pig coronary arteries were treated with sodium nitroprusside (SNP) or atrial natriuretic factor (ANF), relaxants which elevate cGMP, and with isoproterenol or forskolin, relaxants which elevate cAMP. Incubation of the arteries with 10 microM SNP produced a 3.3-fold increase in cGMP without altering cAMP; the cGK activity ratio (-cGMP/+cGMP) in these extracts was increased by 2.6-fold as determined by a newly developed assay, while the cAK activity ratio (-cAMP/+cAMP) was unchanged. The increase in cGK activity ratio by SNP was concentration-dependent and was nearly maximal at 30 s. Treatment of the tissue with 10 nM ANF also increased the cGK activity ratio (2.3-fold), but not that of cAK. 100 microM isoproterenol caused a 2.9-fold elevation of cAMP with no change in cGMP, but both cAK and cGK activity ratios were increased (2.3- and 1.6-fold, respectively). The increase in the cGK activity ratio could be mimicked by cAMP addition to control tissue extracts at the concentration measured in extracts of the isoproterenol-treated tissue. Forskolin (1 and 10 microM) also increased the cGK activity ratio (1.9- and 4.9-fold). The increases in cGK activity observed in extracts suggest that moderate elevation of either cGMP or cAMP causes intracellular cGK activation, thus producing relaxation of vascular smooth muscle.
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PMID:Direct evidence for cross-activation of cGMP-dependent protein kinase by cAMP in pig coronary arteries. 130 58

Most platelet agonists activate and elevate the cytosolic free calcium concentration in human platelets through receptor-dependent mechanisms that are antagonized by cAMP- and cGMP-elevating agents. Nitrovasodilators such as nitroprusside and endothelium-derived relaxing factor are potent cGMP-elevating platelet inhibitors. In the present study, the role of cGMP and cGMP-dependent protein kinase in nitrovasodilator inhibition of ADP- and thrombin-evoked calcium elevation and activation of human platelets was investigated. Preincubation of platelets with 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (8-pCPT-cGMP; a membrane-permeant selective activator of the cGMP-dependent protein kinase that does not significantly affect cGMP-regulated phosphodiesterases) inhibited the thrombin-induced phosphorylation mediated by myosin light chain kinase and protein kinase C. Nitrovasodilator-induced protein phosphorylation in human platelets was distinct from that induced by cAMP-elevating prostaglandins and could be mimicked by 8-pCPT-cGMP. Preincubation of human platelets with nitrovasodilators or 8-pCPT-cGMP inhibited the ADP- and thrombin-evoked calcium elevation in the presence and absence of external calcium. Nitrovasodilators and 8-pCPT-cGMP also inhibited the agonist-induced Mn2+ influx, but stopped-flow experiments indicated that the ADP receptor-operated cation channel was not significantly inhibited. These results suggest that in human platelets nitrovasodilators inhibit the agonist-induced calcium mobilization from intracellular stores and the secondary store-related calcium influx but not the ADP receptor-operated cation channel. The results also suggest that these nitrovasodilator effects are mediated by cGMP and the cGMP-dependent protein kinase.
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PMID:Role of cGMP and cGMP-dependent protein kinase in nitrovasodilator inhibition of agonist-evoked calcium elevation in human platelets. 131 May 37

Affinities of the catalytic subunit (C1) of Saccharomyces cerevisiae cAMP-dependent protein kinase and of mammalian cGMP-dependent protein kinase were determined for the protein kinase inhibitor (PKI) peptide PKI(6-22)amide and seven analogues. These analogues contained structural alterations in the N-terminal alpha-helix, the C-terminal pseudosubstrate portion, or the central connecting region of the PKI peptide. In all cases, the PKI peptides were appreciably less active as inhibitors of yeast C1 than of mammalian C alpha subunit. Ki values ranged from 5- to 290-fold higher for the yeast enzyme than for its mammalian counterpart. Consistent with these results, yeast C1 exhibited a higher Km for the peptide substrate Kemptide. All of the PKI peptides were even less active against the mammalian cGMP-dependent protein kinase than toward yeast cAMP-dependent protein kinase, and Kemptide was a poorer substrate for the former enzyme. Alignment of amino acid sequences of these homologous protein kinases around residues in the active site of mammalian C alpha subunit known to interact with determinants in the PKI peptide [Knighton, D. R., Zheng, J., Ten Eyck, L. F., Xuong, N-h, Taylor, S. S., & Sowadski, J. M. (1991) Science 253, 414-420] provides a structural basis for the inherently lower affinities of yeast C1 and cGMP-dependent protein kinase for binding peptide inhibitors and substrates. Both yeast cAMP-dependent and mammalian cGMP-dependent protein kinases are missing two of the three acidic residues that interact with arginine-18 in the pseudosubstrate portion of PKI. Further, the cGMP-dependent protein kinase appears to completely lack the hydrophobic/aromatic pocket that recognizes the important phenylalanine-10 residue in the N-terminus of the PKI peptide, and binding of the inhibitor by the yeast protein kinase at this site appears to be partially compromised.
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PMID:Structural basis for the low affinities of yeast cAMP-dependent and mammalian cGMP-dependent protein kinases for protein kinase inhibitor peptides. 131 Jun 17


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