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)

8-(p-Chlorophenylthio)-cGMP (8-pCPT-cGMP) and 8-bromo-cGMP were compared with respect to their chemical and biological properties in order to evaluate their potential as selective activators of cGMP-dependent protein kinase (cGMP-PK; EC 2.7.1.37) in intact human platelets. 8-pCPT-cGMP, 8-Br-cGMP and cGMP were shown to be potent and selective activators of purified bovine lung cGMP-PK and of cGMP-PK present in human platelet membranes when compared with the activation of cAMP-dependent protein kinase (cAMP-PK; EC 2.7.1.37). 8-pCPT-cGMP was not hydrolysed by the purified cGMP-stimulated phosphodiesterase (cGS-PDE), cGMP-inhibited phosphodiesterase (cGI-PDE) and Ca(2+)-calmodulin-dependent phosphodiesterase (CaM-PDE), whereas cGMP and, to a lesser extent, 8-Br-cGMP were hydrolysed by all three types of 3',5' cyclic nucleotide phosphodiesterases (EC 3.1.4.17) examined. Also, 8-pCPT-cGMP was not hydrolysed by a human platelet homogenate which contains a high level of the cGMP-specific cGMP-binding phosphodiesterase (cGB-PDE). Additionally, 8-pCPT-cGMP did not activate the cGS-PDE or inhibit the cGI-PDE, whereas half-maximal inhibition of cGI-PDE occurred at 8 microM 8-Br-cGMP. The apparent lipophilicity of 8-pCPT-cGMP was higher than that of 8-Br-cGMP. Extracellular application of 8-pCPT-cGMP to intact human platelets reproduced the pattern of protein phosphorylation induced by sodium nitroprusside (SNP), a cGMP-elevating inhibitor of platelet activation. Quantitatively, 8-pCPT-cGMP was more effective than 8-Br-cGMP in inducing phosphorylation of the 46/50 kDa vasodilator-stimulated phosphoprotein, a major substrate of cGMP-PK in intact platelets. As observed with SNP, pretreatment of human platelets with 8-pCPT-cGMP prevented the aggregation induced by thrombin. The results suggest that 8-pCPT-cGMP is a very potent and selective activator of cGMP-PK in cell extracts and in intact human platelets and, in this respect, is superior to 8-Br-cGMP and other cGMP analogs used for intact cell studies. The data also suggest that inhibition of platelet activation in intact human platelets by nitrovasodilators is mediated by cGMP-PK.
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PMID:Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-para-chlorophenylthio-cGMP. 132 24

The effects of cGMP-dependent protein kinase (G-kinase), a major cellular receptor of cGMP, were investigated in activated human neutrophils. Immunocytochemistry demonstrated that G-kinase translocated from a diffuse localization in the cytoplasm to the cytoskeleton and nucleus after stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP), and transiently co-localized with the intermediate filament protein, vimentin. During this time period, the most remarkable co-localization of G-kinase and vimentin was observed between 1-2.5 min stimulation with fMLP. At that time co-localization of G-kinase and vimentin was predominantly confined to filaments which extended from regions adjacent to the nucleus into the uropod. Distinctive localization for only G-kinase was observed at the microtubule organizing center and euchromatin of the nucleus. The filamentous staining pattern for G-kinase and vimentin was enhanced in the presence of 8-Br-cGMP. Coincident with co-localization of G-kinase and vimentin in adherent neutrophils was a transient increase in cGMP levels and an increase in the phosphorylation of vimentin in fMLP-stimulated cells. The increase in cGMP levels was dependent upon cell adherence, was enhanced by preincubating neutrophils with L-arginine (the precursor for nitric oxide synthesis), and attenuated with the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine. Phosphorylation of vimentin in the fMLP-stimulated neutrophil was observed in the presence or absence of exogenous cGMP, although in the presence of low concentrations of 8-Br-cGMP a more rapid phosphorylation of vimentin was observed that correlated with the enhanced co-localization of G-kinase and vimentin. Phosphorylation of vimentin was not observed in non-activated cells treated with 8-Br-cGMP, suggesting that phosphorylation only occurs when G-kinase is co-localized with vimentin. The presence of the protein kinase C inhibitors, staurosporine or H-7, did not inhibit vimentin phosphorylation during fMLP stimulation, while 8-Br-cGMP enhanced phosphorylation in fMLP-treated cells. This suggests that neither protein kinase C nor cAMP-dependent protein kinase catalyze the phosphorylation of vimentin in neutrophils activated by fMLP. These results indicate that vimentin and G-kinase are co-localized in neutrophils and that vimentin is phosphorylated by G-kinase in response to the co-localization of the two proteins. A model for the targeting of G-kinase and vimentin is presented which hypothesizes that the transient redistribution of G-kinase may regulate neutrophil activation.
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PMID:Vimentin is transiently co-localized with and phosphorylated by cyclic GMP-dependent protein kinase in formyl-peptide-stimulated neutrophils. 165 55

We investigated cellular mechanisms mediating the parathyroid hormone (PTH)-induced increase in cytosolic free Ca2+ concentration ([Ca2+]i) in isolated perfused rabbit connecting tubules. Prior and/or concomitant exposure to 0.5 mM of N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-8), a cyclic nucleotide-dependent protein kinase inhibitor, abolished the rise in [Ca2+]i produced by 0.1 nM PTH in five connecting tubules and suppressed it by approximately 50% in another five. In the latter, there was a delayed onset in the rise of [Ca2+]i. Such responses contrasted to the prompt increase in [Ca2+]i in PTH-stimulated control tubules. However, when H-8 was withdrawn, [Ca2+]i rose within minutes to reach a plateau value similar to the uninhibited response to PTH in controls, indicating rapidly reversible inhibition by H-8. In an otherwise identical protocol, 0.5 mM H-8 also reversibly suppressed the rise in [Ca2+]i induced by 0.175 mM 8-Br-cAMP. In contrast to the stimulatory effect of 8-Br-cAMP on [Ca2+]i, 1 mM 8-Br-cGMP caused no increase. At a concentration of 0.4 mM, the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS), a well-characterized cAMP-dependent protein kinase inhibitor, totally abolished the rise in [Ca2+]i caused by 0.1 nM PTH. We conclude that a cAMP-dependent protein kinase plays an important role in the PTH-stimulated rise in [Ca2+]i in the rabbit connecting tubule. Since the increase in [Ca2+]i was shown previously to depend on extracellular Ca2+, we propose that cAMP-dependent protein phosphorylation is important in mediating PTH-stimulated Ca2+ fluxes across plasma membranes of connecting tubule cells.
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PMID:Evidence for cAMP-dependent protein kinase in mediating the parathyroid hormone-stimulated rise in cytosolic free calcium in rabbit connecting tubules. 253 2

The regulation of the cytosolic calcium concentration was investigated in freshly isolated adult bovine tracheal smooth muscle cells using fura 2. These cells contain 1.1 and 1.8 pmol of cGMP kinase and cAMP kinase per mg protein, respectively. Carbachol, histamine, serotonin, isoproterenol, and salbutamol increased the cytosolic calcium in a dose-dependent manner from 79 nM to about 650 nM. Preincubation of these cells for 20 min with isoproterenol, forskolin, 8-Br-cAMP and 8-(4-Cl-phenyl)thio-cAMP did not lower carbachol-induced increases in cytosolic calcium concentration, whereas the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, the atrionatriuretic factor, isobutylmethylxanthine, and 8-Br-cGMP lowered cytosolic calcium. The active fragment of cGMP kinase, but not the catalytic subunit of cAMP kinase lowered carbachol-induced calcium levels. Carbachol released calcium from intracellular stores and increased calcium influx from the extracellular space. The influx was inhibited by preincubation with the calcium channel blockers nitrendipine or gallopamil. Both carbachol-stimulated pathways were suppressed by 8-Br-cGMP. Isoproterenol increased only the influx of calcium from the outside by a channel which was blocked by calcium channel blockers or 8-Br-cGMP. Forskolin and 8-Br-cAMP lowered carbachol- and isoproterenol-stimulated increases in calcium when added shortly before or after the addition of the agonist. In addition, isoproterenol decreased carbachol-stimulated calcium levels when added 10 s after carbachol. The calcium stimulatory effect of isoproterenol was abolished by preincubation of the cells with pertussis toxin or cholera toxin. These results show (a) that the beta 2-adrenoceptor couples in isolated tracheal smooth muscle cells to a dihydropyridine- and pertussis toxin-sensitive calcium channel; (b) that the same channel is opened by carbachol; (c) that cGMP kinase is very effective in decreasing elevated cytosolic calcium concentrations, whereas cAMP-dependent protein kinase has a variable effect on stimulated cytosolic calcium levels.
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PMID:Regulation of cytosolic calcium by cAMP and cGMP in freshly isolated smooth muscle cells from bovine trachea. 284 48

Cardiac sarcolemmae from guinea pig ventricles were purified and incubated with cGMP-dependent protein kinase. In the presence of the purified kinase plus 10(-5) M cGMP or 8-Br-cGMP, a protein of approximately 50 kD, (Kilodalton) was phosphorylated. This membrane-associated cGMP-dependent protein kinase substrate is similar in MW to the regulatory subunit of the cAMP-dependent protein kinase, which is known to be a substrate for the cGMP-dependent protein kinase. Thus, this substrate, the identity of which remains to be proven, may be a possible mediator of cGMP-mediated control of cardiac function.
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PMID:Cardiac sarcolemmal substrate of the cGMP-dependent protein kinase. 285 60

Cyclic GMP depresses Ba2+ current through high-voltage-activated Ca2+ channels (ICa) in acutely isolated hippocampal neurons. The effect is produced by intra-, but not extracellular, cGMP or by 5' GMP. The membrane-permeant derivative, 8-Br-cGMP, produces a reversible suppression. The effect of 8-Br-cGMP is similar to phorbol ester-induced ICa depression, except that ICa depression due to 8-Br-cGMP is not blocked by protein kinase inhibitors H-8 or H-7, whereas phorbol ester effects are. The data suggest that cGMP depresses ICa by a cGMP-kinase- and protein kinase C (PKC)-independent mechanism. Cyclic AMP, which enhances ICa, and the cyclic nucleotide phosphodiesterase inhibitor, IBMX, both antagonize ICa depression induced by 8-Br-cGMP, but not that due to phorbol esters. Cyclic IMP, a more potent activator of phosphodiesterase than of cGMP-dependent protein kinase, is also a powerful depressant of ICa. We conclude that cGMP-induced depression of ICa is mediated by activation of cyclic nucleotide phosphodiesterase with consequent reduction of intracellular cAMP.
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PMID:Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. 285 1

Nitrates probably induce vasorelaxation via a rise of cytosolic cGMP, and subsequent phosphorylation of target proteins by cGMP-dependent protein kinase. A dual type of action by this mechanism seems likely: cGMP-dependent protein kinase relaxes chemically skinned vascular smooth muscle which has no functioning cell membrane. Thus, the contractile apparatus with its regulatory and contractile proteins may be one of the targets for their action. Calcium visualization techniques using aequorin or quin-2, and ion flux studies showing suppression of Ca2+-dependent 86Rb efflux by nitrates and 8-Br-cGMP suggest that the cytosolic calcium level is another target for their action. Whether this lowering of intracellular calcium occurs via cGMP-dependent activation of the sarcolemmal Ca2+ extrusion ATPase, requires confirmation.
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PMID:Mode of action of nitrates at the cellular level. 302 2

Several aspects of the mode of action of direct vasodilators are discussed. Nitro-compounds probably act via an intracellular formation of S-nitrosothiols, which stimulate cellular guanylate cyclase. Doubts, however, arise with regard to a generalization of this concept, e.g., methylene blue, an inhibitor of guanylate cyclase, interferes potently with the vasorelaxant action of nitroglycerin, but not with that of nitroprusside and sodium nitrite in KCl-stimulated rabbit aorta. Nitro-compounds do not interfere with transmembrane calcium movements. Hyperpolarization of the vascular smooth-muscle membrane, although reported to occur with nitroprusside, does not seem to be a common feature of the nitro-compounds. On the other hand, all nitro-compounds tested interfered with the noradrenaline-induced increase in 36-Cl steady-state exchange in rabbit aorta, and this effect could be mimicked by 8-Br-cGMP. Chemically skinned vascular smooth muscle was relaxed by pure cGMP-dependent protein kinase, but this effect requires confirmation. The action of hydralazine is augmented in chemically sympathectomized arteries and blocked by purines, such as adenosine, pointing to modulating role of purine-like compounds released from sympathetic nerve endings. The direct vasodilator action of hydralazine consists of a predominantly inhibitory effect on pharmacomechanical coupling. Membrane hyperpolarization with hydralazine has been reported. In addition to having direct effects on vascular smooth muscle, hydralazine can interfere with transmitter release by a prejunctional mechanism, and part of its vasorelaxant action seems to depend on the integrity of the endothelium in vascular smooth muscle.
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PMID:Direct vasodilators with unknown modes of action: the nitro-compounds and hydralazine. 608 7

Forskolin (FOR), a diterpene activator of adenylate cyclase, produced time- and dose-dependent increases in cAMP, cAMP-dependent protein kinase activation and relaxation in the contracted rat aorta but had no effect on cGMP levels. Nitroprusside (NP) increased cGMP levels and relaxation but had no effect on cAMP levels. cAMP-dependent protein kinase activation was seen with higher concentrations of NP. Major differences were observed in the modes of action of the two compounds: (1) the time course of relaxation to FOR was slower than that to NP (15 min vs. 3 min) even though the cAMP-dependent protein kinase activity ratio was maximally elevated at 3 min after the addition of FOR; (2) FOR and dibutyryl cAMP prevented contraction to both norepinephrine (NE) and KCl whereas NP and 8-bromo-guanosine 3',5'-monophosphate (8-Br-cGMP) were more effective in preventing contraction to NE than to KCl. In addition, the analog of cGMP was more effective in preventing contraction to KCl at lower concentrations of external Ca2+ while the analog of cAMP prevented contraction to KCl at all concentrations of Ca2+ equally. Nevertheless, some similarities in the actions of FOR and NP were apparent in that both agents relaxed the NE-contracted aorta more effectively than the KCl-contracted aorta, and both agents relaxed aorta contracted with lower doses of NE more effectively than that contracted with high doses of NE. These results suggest that although some similarities in the relaxing action of rat aorta by FOR and NP exist, major differences are apparent which suggests that the two compounds exert these effects through unique biochemical mechanisms.
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PMID:A comparison of the effects of forskolin and nitroprusside on cyclic nucleotides and relaxation in the rat aorta. 608 62

Contractions of the guinea pigs vas deferens were induced by field stimulation and the effects of derivatives of cGMP were tested on the contraction-relaxation cycle. Relaxation was induced by 8-Br-cGMP and O2'-mb-cGMP. On the contrary, db-cGMP and N2-mb-cGMP potentiated the contraction. The relaxant effect of 8-Br-cGMP was not mimicked by 8-Br-5'GMP, instead the latter caused the opposite effect. Since neither 8-Br-cGMP nor db-cGMP affected the release of norepinephrine on field stimulation the cGMP derivatives induced their effects at a postsynaptic site. 8-Br-cGMP was found to be 100-fold more potent than cGMP to simulate protein kinase activity in crude extracts from guinea pig was deferens. N2-mb-cGMP and O2'-mb-cGMP were approximately equipotent to cGMP while db-cGMP was less active. 8-Br-5'-GMP did not stimulate the protein kinase. It is suggested that the results support the hypothesis that cGMP acts as a relaxant in the smooth muscle of the vas deferens. The potentiation caused by db-cGMP and N2-mb-cGMP on contractions could be dependent on the substitution in the guanine moiety of the molecules with the butyryl group. Their effect was thus probably unrelated to a specific cGMP effect.
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PMID:Effect of cGMP derivatives on contraction relaxation cycle, release of norepinephrine and protein kinase activity in guinea pig vas deferens. 627 Sep 55


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