Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 The effects of two 8-substituted analogues of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were compared with those of forskolin and isoprenaline on [3H]-noradrenaline release and vasoconstriction induced by electrical field stimulation (24 pulses at 0.4 Hz, 200 mA, 0.3 ms duration) in the rat tail artery, in the absence and in the presence of protein kinase inhibitors. 2 8-Bromo-adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP, 10-300 microM), 8-(4-chlorophenyl-thio)-adenosine 3':5' cyclic monophosphate (8-pCPT-cyclic AMP, 3-300 microM), forskolin (0.3-10 microM) and isoprenaline (1 nM-1 microM) all concentration-dependently enhanced stimulation-induced [3H]-noradrenaline release. The effect of cyclic AMP analogues was larger (2.5 fold at 300 microM) than those of cyclic AMP elevating drugs (1.6 fold at 10 microM for forskolin and 1.5 fold at 30 nM for isoprenaline). 3 At concentrations active at the prejunctional level, the four drugs had differential effects on stimulation-induced vasoconstriction, which was enhanced by the two cyclic AMP analogues, decreased by forskolin and not significantly altered by isoprenaline. 4 The [3H]-noradrenaline release-enhancing effects of 8-bromo-cyclic AMP, forskolin and isoprenaline were significantly decreased by the cyclic AMP-dependent protein kinase (PKA) inhibitor (N-[2-((3-(4-bromophenyl)-2-propenyl)-amino)-ethyl]-5- isoquinolinesulphonamide, di-hydrochloride) (H-89; 100 nM). By contrast they were unaffected by the cyclic GMP-dependent protein kinase (PKG) inhibitor, 8-bromo-guanosine 3':5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-bromo-cyclic GMPS; 10 microM). By contrast they were unaffected by the cyclic GMP-dependent protein kinase (PKG) inhibitor,8-bromo-guanosine 3':5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-bromo-cyclic GMPS; 10 MicroM).At the same concentrations the PKA inhibitor attenuated only the nerve-induced vasoconstrictor responses obtained in the presence of 8-bromo-cyclic AMP, whereas the PKG inhibitor did not modify that obtained in the presence of 8-bromo-cycic AMP or forskolin.5. Exposure to the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (1 MicroM) enhanced nerve-evoked [3H]-noradrenaline release, and this effect was decreased by the PKC inhibitor, 2-[1-(3-dimethylaminopropyl)-indol-3-yl]-3-(-indol-3-yl)-maleimide (GF 109203X; 100 nM). However, the latter drug did not modify the enhancing effect of 8-bromo-cyclic AMP on [3H]-noradrenaline release.6. It is concluded that activation of cyclic AMP-dependent protein kinase is involved in the enhancing effect of cyclic AMP-elevating compounds on prejunctional release of noradrenaline. In addition the results provide no clear-cut evidence for a vasodilator role of PKA.
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PMID:Effects of cyclic AMP and analogues on neurogenic transmission in the rat tail artery. 800 6

The aim of the present study was to determine the phosphorylation of the purified ryanodine receptor-calcium release channel (RyR) of rabbit skeletal muscle sarcoplasmic reticulum by the cAMP-dependent protein kinase (PK-A), cGMP-dependent protein kinase (PK-G) and Ca(2+)-, CaM-dependent protein kinase (PK-CaM) and the localization of phosphorylation sites. Phosphorylation was highest with PK-A (about 0.9 mol phosphate/mol receptor subunit), between one-half to two-thirds with PK-G and between one-third and more than two-thirds with PK-CaM. Phosphoamino acid analysis revealed solely labeled phosphoserine with PK-A and PK-G and phosphoserine and phosphothreonine with PK-CaM. Reverse-phase high-performance liquid chromatography (HPLC) of cyanogen bromide/trypsin digests of the phosphorylated RyR (purified by gel permeation HPLC) and two-dimensional peptide maps revealed one major phosphopeptide by PK-A and PK-G phosphorylation and several labeled peaks by PK-CaM phosphorylation. Automated Edman sequence analysis of the major phosphopeptide obtained from PK-A and PK-G phosphorylation and one phosphopeptide obtained from PK-CaM phosphorylation yielded the sequence KISQTAQTYDPR (residues 2841-2852) with serine 2843 as phosphorylation site (corresponding to the consensus sequence RKIS), demonstrating that all three protein kinases phosphorylate the same serine residue in the center of the receptor subunit, a region proposed to contain the modulator binding sites of the calcium release channel.
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PMID:Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase. 838 Mar 42

The present study was designed to investigate whether in vivo and in vitro erythropoietin (EPO) production is modulated by nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP). Serum levels of EPO in ex-hypoxic polycythemic mice were significantly increased after injections of 200 micrograms/kg sodium nitroprusside for 4 d. One injection of NG-nitro-L-arginine methyl ester (L-NAME) produced a significant dose-related decrease in serum levels of EPO in ex-hypoxic polycythemic mice in response to hypoxia. When EPO producing Hep3B cells were incubated in 1% O2 for 30 min, cGMP levels in the Hep3B cells were significantly elevated, compared with cells incubated in 20% O2. The elevation of cGMP by hypoxia was inhibited by L-NAME (100 microM). Sodium nitroprusside (10 and 100 microM) and NO (2 microM) also significantly increased cGMP levels in Hep3B cells. L-NAME, LY 83583 (6-Anilino-5,8-quinolinedione, a soluble guanylate cyclase inhibitor), and Rp-8-Bromo-cGMPS (Rp-8-Bromo-guanosine 3',5'-cyclic monophosphothioate, a cGMP-dependent protein kinase inhibitor) significantly inhibited the hypoxia-induced increase in medium levels of EPO in Hep3B cells. 8-Bromo-cGMPS produced a dose-dependent decrease in EPO messenger RNA levels in Hep3B cells in response to hypoxia. 8-Bromo-cGMP (10(-3) M) produced significant increases in medium levels of EPO in Hep3B cell cultures incubated under normoxic conditions, which was enhanced by the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (0.2 mM). These results suggest that NO and cGMP may interact in modulating hypoxic stimulation of EPO production.
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PMID:Interaction of nitric oxide and cyclic guanosine 3',5'-monophosphate in erythropoietin production. 839 29

The effects of cyclic AMP (cAMP) and cyclic GMP (cGMP) on dihydropyridine sensitive Ca2+ channels were investigated under voltage-clamp in defolliculated Pleurodeles oocytes. Intracellular injection of cAMP or extracellular application of the permeable cAMP analogue (8-Bromo cAMP, 8Br-cAMP) decreased the Ba current (IBa). This effect on IBa was blocked by the injection of protein kinase A inhibitor. Similar results were found upon internal application of the catalytic subunit of protein kinase A. In contrast, the injection of cGMP or perfusion of 8Br-cGMP increased IBa amplitude. The increase of IBa by 8Br-cGMP was blocked by the injection of the selective inhibitor of protein kinase G (KT5823). These results support the hypothesis that the basal Ba current amplitude of Pleurodeles oocytes is under the control of Protein Kinases A (PKA) and G (PKG) activity. This regulation of Ca2+ channels by the second messengers, and particularly by cAMP may reflect an important step in the maturation processus of Pleurodeles oocytes.
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PMID:Regulation of endogenous Ca2+ channels by cyclic AMP and cyclic GMP-dependent protein kinases in Pleurodeles oocytes. 906 5

(Rp)-8-Bromo-guanosine 3',5'-cyclic monophosphorothioate (Rp-8-Br-cGMPS) inhibited competitively both isozymes of type I alpha and I beta cGMP-dependent protein kinase (cGMP-kinase) purified from porcine aorta with apparent Ki values (microM) of 3.7 for I alpha and 1.8 for I beta. The compound also inhibited bovine heart type II cAMP-dependent protein kinase (cAMP-kinase), but with a Ki of 25 microM. Thus, it is a selective inhibitor of cGMP-kinase. In alpha-toxin-skinned smooth muscle preparations from rat mesenteric artery, 8-Br-cGMP (10(-7) M) and 8-Br-cAMP (10(-6) M) produced a rightward shift of the concentration-contraction curves for Ca2+, denoting a decrease in Ca2+ sensitivity of the contractile elements. The shift by 8-Br-cAMP as well as by 8-Br-cGMP was completely reversed by Rp-8-Br-cGMPS, while a selective inhibitor of activation of cAMP-kinase, (Rp)-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPS), was without effects on the shift produced by these two compounds. These findings indicate the pivotal role that the activation of cGMP-kinase plays in the production of a decrease in Ca2+ sensitivity of contractile elements.
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PMID:cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery. 910 79

Atrial natriuretic peptide (ANP) is known to suppress platelet-derived growth factor (PDGF)-stimulated proliferation of rat cultured vascular smooth muscle cells. The present study examined whether ANP inhibits the PDGF receptor (PDGFR) tyrosine kinase activation, an initial event for PDGF cellular signaling. ANP reduced the in vivo tyrosine phosphorylation of PDGFR stimulated by PDGF in a dose-dependent manner. This effect was not due to the reduction in PDGFR protein as detected by immunoblot analysis. 8-Bromo-cyclic GMP, a membrane-permeable 3',5'-cyclic monophosphate (cGMP) derivative, mimicked the action of ANP. HS-142-1, an antagonist for guanylate cyclase A (GC-A) and B, co-incubated with ANP, restored the PDGF-induced PDGFR autophosphorylation. The effect of ANP was also observed in the presence of a protein tyrosine phosphatase inhibitor, sodium orthovanadate. To confirm that ANP exerts its action by inhibiting protein tyrosine kinase (PTK), an in vitro kinase assay was performed. Cyclic GMP inhibited PTK activity of PDGFR partially purified by lectin affinity chromatography. In contrast, PTK activity in immobilized PDGFR immunocomplexes was not inhibited by cGMP. However, exogenous cGMP dependent protein kinase (PKG) reduced the PTK activity in the presence of cGMP. These results demonstrate that ANP suppresses PDGFR PTK through GC-A probably by activating PKG. This may be an important mechanism by which ANP exerts its anti-proliferative action antagonizing PDGF.
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PMID:Inhibition of platelet-derived growth factor receptor tyrosine kinase by atrial natriuretic peptide. 926 90

The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on L-type Ca current (ICa) was investigated in a study of rabbit ventricular myocytes using the whole-cell patch-clamp technique. Intracellular application of cGMP (100 MUm) increased ICa in the absence of isoprenaline or forskolin. 8-Bromo-cGMP (100 muM) and 8-(4-chlorophenylthio)-cGMP (8-pCPT-cGMP, 400 muM), relatively specific stimulators of cGMP-dependent protein kinase (cGMP-PK), also increased ICa. The stimulatory effect of 8-pCPT-cGMP was suppressed by Rp-8-chlorophenylthio-cGMP (400 muM), a phosphodiesterase-resistant cGMP-PK inhibitor. When ICa was increased by bath application of the non-specific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 100 muM), 8-pCPT-cGMP (400 muM) resulted in additional stimulation of ICa. In the presence of 8-pCPT-cGMP, additional applications of isoprenaline (1 muM) or forskolin (1 muM) induced a further increase in ICa. From these results, it could be concluded that the activation of cGMP-dependent protein kinase is involved in the facilitation of ICa by cGMP in rabbit ventricular myocytes.
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PMID:cGMP facilitates calcium current via cGMP-dependent protein kinase in isolated rabbit ventricular myocytes. 942 95

Cyclic nucleotides are known to modify voltage-gated (L-type) Ca2+ channel activity in vascular smooth muscle cells, but the exact mechanism(s) underlying these effects is not well defined. The purpose of the present study was to investigate the modulatory role of the cAMP- and cGMP-dependent protein kinase (PKA and PKG, respectively) pathways in Ca2+ channel function by using both conventional and perforated-patch-clamp techniques in rabbit portal vein myocytes. The membrane-permeable cAMP derivative, 8-bromo cAMP (0.1 to 10 micromol/L), significantly increased (14% to 16%) peak Ba2+ currents, whereas higher concentrations (0.05 to 0.1 mmol/L) decreased Ba2+ currents (23% to 31%). In contrast, 8-bromo cGMP inhibited Ba2+ currents at all concentrations tested (0.01 to 1 mmol/L). Basal Ca2+ channel currents were significantly inhibited by the PKA blocker 8-Bromo-2'-O-monobutyryladenosine-3',5'-monophosphorothioate, Rp-isomer (Rp 8-Br-MP cAMPS, 30 micromol/L) and enhanced by the PKG inhibitor beta-Phenyl-1,N2-etheno-8-bromoguanosine-3',5'-monophosphorothioate, Rp-isomer (Rp-8-Br PET cGMPS, 10 nmol/L). In the presence of Rp 8-bromo PET cGMPS (10 to 100 nmol/L), both 8-bromo cAMP (0.1 mmol/L) and 8-bromo cGMP (0.1 mmol/L) enhanced Ba2+ currents (13% to 39%). The excitatory effect of 8-bromo cGMP was blocked by Rp 8-bromo MB-cAMPS. Both 8-bromo cAMP (0.05 mmol/L) and forskolin (10 micromol/L) elicited time-dependent effects, including an initial enhancement followed by suppression of Ba2+ currents. Ba2+ currents were also enhanced when cells were dialyzed with the catalytic subunit of PKA. This effect was reversed by the PKA blocker KT 5720 (200 nmol/L). Our results suggest that cAMP/PKA stimulation enhances and cGMP/PKG stimulation inhibits L-type Ca2+ channel activity in rabbit portal vein myocytes. Our results further suggest that both cAMP and cGMP have a primary action mediated by their own kinase as well as a secondary action mediated by the opposing kinase.
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PMID:Modulation of Ca2+ channels by cyclic nucleotide cross activation of opposing protein kinases in rabbit portal vein. 952 60

Large conductance, voltage- and Ca2+-sensitive K+ (maxi-K(Ca)) channels play an important role in the regulation of vascular smooth muscle excitability and contractility. The activity of maxi-K(Ca) channels is modified by a variety of intracellular messengers including cGMP, as well as by voltage and Ca2+. In the present study, we investigated the functional relevance of maxi-K(Ca) channels in atrial natriuretic peptide (ANP)-mediated vasorelaxation in the isolated rat mesenteric artery. ANP produced concentration-dependent relaxation in the de-endothelialized rat mesenteric artery. Iberiotoxin, a specific blocker of maxi-K(Ca) channels, greatly attenuated the ANP-induced vasorelaxation. Similarly, a large portion of the vascular relaxation induced by 8-Bromo-cGMP, a membrane permeable analogue of cGMP, was inhibited by iberiotoxin. These results indicate that activation of maxi-K(Ca) channels contributes substantially to the vascular relaxation produced by ANP in the rat mesenteric artery. Intracellular cGMP, increased by ANP, and the subsequent activation of cGMP-dependent protein kinase (PKG) may play a central role in the activation of maxi-K(Ca) channels in the ANP-produced vascular relaxation.
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PMID:Involvement of maxi-K(Ca) channel activation in atrial natriuretic peptide-induced vasorelaxation. 968 49

We examined whether nitric oxide (NO), a possible cardioprotective substance, can increase the production of interstitial adenosine in the ventricular myocardium. A flexibly mounted microdialysis technique was used to measure the concentration of interstitial adenosine and to assess the activity of ecto-5'-nucleotidase in in vivo rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and perfused with Tyrode solution containing adenosine 5'-monophosphate (AMP) at a rate of 1.0 microl min-1. The concentration of adenosine in the effluent (dialysate) was measured by high-performance liquid chromatography. Dialysate adenosine obtained during perfusion with the AMP-containing solution through the probe originated from the hydrolysis of AMP by endogenous ecto-5'-nucleotidase, and the level of adenosine reflected the activity of ecto-5'-nucleotidase in the tissue. S-Nitroso-N-acetylpenicillamine (SNAP, 0.3-3 mM), an NO donor, increased the dialysate adenosine measured in the presence of AMP (100 microM) in a concentration-dependent manner. However, in the presence of an NO-oxidizing agent, 2-(4-carboxyphenyl-4,4,5, 5-tetramethylimidazoline)-1-oxyl 3-oxide (carboxy-PTIO, 1 mM), the effect of SNAP was abolished. Another NO donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409, 1 mM) also increased adenosine production. 8-Bromo-cGMP (0.1-3 mM), a membrane-permeable cGMP analogue and a potent activator of cGMP-dependent protein kinase, increased the level of AMP-primed dialysate adenosine in a concentration-dependent manner. These results suggest that NO facilitates the production of interstitial adenosine in rat hearts in situ, via cGMP-mediated activation of ecto-5'-nucleotidase.
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PMID:NO and cGMP facilitate adenosine production in rat hearts via activation of ecto-5'-nucleotidase. 979 17


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