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)

Achatin-I (Gly-D-Phe-Ala-Asp), a tetrapeptide having a D-phenylalanine residue and isolated from Achatina ganglia, has been proposed as an excitatory neurotransmitter of Achatina neurones. In the present study, it was demonstrated using Achatina giant neurones that achetin-I, perfused at alow concentration, enhanced an inward current (Iin) caused by 5-hydroxytryptamine (fast component) and an outward current (Iout) caused by FMRFamide (Phe-Met-Arg-Phe-NH2), and that this peptide suppressed an Iin caused by oxytocin, and Iout caused by acetylcholine and APGW-amide (Ala-Pro-Gly-Trp-NH2). These findings indicate that achatin-I acts not only as a neurotransmitter but also as a neuromodulator for these neurones. In the preliminary experiments, it was shown that an Iin caused by achatin-I on an Achatina giant neurone type, PON (periodically oscillating neurone), was suppressed by H-89 (a PKA inhibitor) and W-7 (calmodulin inhibitor), and that an Iin caused by achatin-I on v-RCON (ventral-right cerebral distinct neurone) was suppressed by KT5823 (PKG inhibitor), suggesting that achatin-I acts on PON via the cyclic AMP-PKA system and on v-RCON via the cyclic GMP-PKG system. Moreover, calmodulin would play a role to produce the Iin for achatin-I on PON via the system mentioned.
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PMID:Further study on the effects of achatin-I, an Achatina endogenous neuroexcitatory tetrapeptide having a D-phenylalanine residue, on Achatina neurones. 885 10

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

1. The involvement of cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKC) in the effects of cyclic AMP-elevating agents on vascular smooth muscle relaxation, cyclic nucleotide dependent-protein kinase activities and ATP-induced calcium signalling ([Ca2+]i was studied in rat aorta. Cyclic AMP-elevating agents used were a beta-adrenoceptor agonist (isoprenaline), a phosphodiesterase 3 (PDE3) inhibitor (SK&F 94120) and a PDE4 inhibitor (rolipram). 2. In rat intact aorta, the relaxant effect induced by isoprenaline (0.01-0.03 microM) was decreased by a specific inhibitor of PKA, H-89, whereas a specific inhibitor of PKG, Rp-8-Br-cyclic GMPs, was without effect. NO significant difference in PKA and PKG activity ratios was detected in aortic rings when isoprenaline 10 microM was used. At the same concentration, isoprenaline did not modify ATP-induced changes in [Ca2+]i in smooth muscle cells. Neither H-89 nor Rp-8-Br-cyclic GMPs modified this response. These findings suggest that PKA is only involved in the relaxant effect induced by low concentrations of isoprenaline (0.01-0.3 microM), whereas for higher concentrations, other mechanisms independent of PKA and PKG were involved. 3. The relaxant effects induced by SK&F 94120 and rolipram were inhibited by Rp-8-Br-cyclic GMPS with no significant effect of H-89. Neither SK&F 94120, nor rolipram at 30 microM significantly modified the activity ratios of PKA and PKG. Rolipram inhibited the ATP-induced transient increase in [Ca2+]i. This decrease was abolished by Rp-8-Br-cyclic GMPS whereas H-89 had no significant effect. These results suggests that PKG is involved in the vascular effects induced by the inhibitors of PDE3 and PDE4. Moreover, since it was previously shown that PDE3 and PDE4 inhibitors only increased cyclic AMP levels with no change in cyclic GMP level, these data also suggest a cross-activation of PKG by cyclic AMP in rat aorta. 4. The combinations of 5 microM SK&F 94120 with rolipram markedly potentiated the relaxant effect of rolipram. This relaxation was decreased by H-89 and not significantly modified by Rp-8-Br-cyclic GMPS. Moreover, the association of the two PDE inhibitors significantly increased the activity ratio of PKA without changing the PKG ratio. The present findings show that PKA rather than PKG is involved in this type of vasorelaxation. The differences in the participation of PKA vs PKG observed when inhibitors of PDE3 and PDE4 were used alone or together could be due to differences in the degree of accumulation of cyclic AMP, resulting in the activation of PKA or PKG which are differently localized in the cell. 5. These findings support for both PKA and PKG in cyclic AMP-mediated relaxation in raT aorta. Their involvement depends on the cellular pathway used to increase the cyclic AMP level.
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PMID:Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation. 929 42

Dopamine (DA) and fencamfamine (FCF) modulatory action on Na,K-ATPase and Mg-ATPase activity were evaluated in rat striatum. DA and FCF induced a decrease in Na,K-ATPase, without affecting Mg-ATPase activity. The effect of FCF was dose-dependent from 10 to 100 microM, with an IC50 of 4.7 x 10(-5) M. Furthermore, the effect of FCF (100 microM) increasing AMPc levels, but not GMPc, was nonadditive with that of DA (10 microM), which is consistent to a common site of action. The 8-bromo-cyclic AMP also induced a specific reduction in the Na,K-ATPase activity. The reduction of Na,K-ATPase induced by FCF (100 microM) was blocked by either SCH 23390 or sulpiride, which are D1 and D2 receptor antagonists. The decrease in striatal NA,K-ATPase activity induced by FCF was blocked by KT 5720, a selective inhibitor of cyclic AMP-dependent protein kinase (PKA), but not by KT 5823, a selective inhibitor of cyclic GMP-dependent protein kinase (PKG). Otherwise, KT 5720 or KT 5823 did not produce any change in Na,K-ATPase or Mg-ATPase activity. These data suggest that FCF reduces Na,K-ATPase activity through cyclic AMP-dependent changes in protein phosphorylation via a PKA mechanism.
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PMID:Fencamfamine modulates sodium, potassium-ATPase through cyclic AMP and cyclic AMP-dependent protein kinase in rat striatum. 982 1

The ability of cGMP-dependent protein kinases (cGKs) to activate cAMP response element (CRE)-dependent gene transcription was compared with that of cAMP-dependent protein kinases (cAKs). Although both the type Ibeta cGMP-dependent protein kinase (cGKIbeta) and the type II cAMP-dependent protein kinase (cAKII) phosphorylated the cytoplasmic substrate VASP (vasodilator- and A kinase-stimulated phosphoprotein) to a similar extent, cyclic nucleotide regulation of CRE-dependent transcription was at least 10-fold higher in cAKII-transfected cells than in cGKIbeta-transfected cells. Overexpression of each kinase in mammalian cells resulted in a cytoplasmic localization of the unactivated enzyme. As reported previously, the catalytic (C) subunit of cAKII translocated to the nucleus following activation by 8-bromo-cyclic AMP. However, cGKIbeta did not translocate to the nucleus upon activation by 8-bromo-cyclic GMP. Replacement of an autophosphorylated serine (Ser79) of cGKIbeta with an aspartic acid resulted in a mutant kinase with constitutive kinase activity in vitro and in vivo. The cGKIbetaS79D mutant localized to the cytoplasm and was only a weak activator of CRE-dependent gene transcription. However, an amino-terminal deletion mutant of cGKIbeta was found in the nucleus as well as the cytoplasm and was a strong activator of CRE-dependent gene transcription. These data suggest that the inability of cGKs to translocate to the nucleus is responsible for the differential ability of cAKs and cGKs to activate CRE-dependent gene transcription and that nuclear redistribution of cGKs is not required for NO/cGMP regulation of gene transcription.
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PMID:Cyclic AMP- and cyclic GMP-dependent protein kinases differ in their regulation of cyclic AMP response element-dependent gene transcription. 1008 70

Several of the hepatic microsomal cytochromes P-450 (CYP) including CYP3A are inducible by phenobarbital (PB). However, the intracellular pathways involved in the action of PB on CYP3A remain poorly known. With the aim to unravel some of the main aspects of PB signaling, we first devised a simple model of mouse cultured primary hepatocytes in which CYP3A mRNA and protein were strongly induced by PB in the absence of dexamethasone and were at maximum levels after a 48-h treatment with a 2-mM dose of PB. Under these culture conditions, we studied the effects of inhibitors and activators of different protein kinases or phosphatases on CYP3A mRNA and protein induction by PB. CYP3A-induced expression was inhibited by activators of cyclic AMP-dependent protein kinase (PKA) (dibutyryl-cyclic AMP and forskolin) whereas inhibition of PKA by PKA inhibitor enhanced induction. 8-br-cGMP produced effects similar to the activators of PKA, and so did the specific inhibitor of cGMP-dependent protein kinase, beta-phenyl-1, N(2)-etheno-8-bromoguanosine-3,5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-PET-cGMPS). Inhibition of Ca(2+)/calmodulin-dependent protein kinase by KN-62 or the intracellular Ca(2+) chelator BAPTA-AM produced an inhibition of CYP3A induction by PB. Specific inhibitors of protein kinase C, mitogen-activated protein kinase kinase, phosphatidylinositol-3-kinase, or serine/threonine phosphatase did not produce any effect. Taken together, our results suggest that CYP3A induction by PB is regulated positively by calmodulin-dependent protein kinase and cGMP-dependent protein kinase, and negatively by PKA in mouse hepatocytes in primary culture.
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PMID:Involvement of cyclic nucleotide- and calcium-regulated pathways in phenobarbital-induced cytochrome P-450 3A expression in mouse primary hepatocytes. 1045 3

Although it is widely agreed that cyclic AMP is necessary for the full expression of long-term potentiation of synaptic strength, it is unclear whether cyclic AMP or cyclic AMP-dependent protein kinase (PKA) play roles in the induction of long-term depression (LTD). We show here that two PKA inhibitors, H-89 (10 microM) and KT5720 (1 microM), are unable to block induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Rather, H-89 enhanced the magnitude of LTD induced by submaximal low-frequency stimulation. Raising [cGMP] with zaprinast (20 microM), a selective type V phosphodiesterase inhibitor, reversibly depressed synaptic potentials. However, coapplication of H-89 plus zaprinast converted this to a robust LTD that depended critically on activation of cyclic GMP-dependent protein kinase (PKG). Chemically induced LTD is activity-independent because it could be induced without stimulation and in tetrodotoxin (0.5 microM). Additionally, chemical LTD did not require activation of N-methyl-D-aspartate or GABA receptors and could be reversed by LTP. Stimulus-induced LTD occluded chemical LTD, suggesting a common expression mechanism. In contrast to bath application, postsynaptic infusion of H-89 into CA1 pyramidal neurons did not enhance LTD, suggesting a presynaptic site of action. Further evidence for a presynaptic locus was supplied by experiments where H-89 applied postsynaptically along with bath application of zaprinast was unable to produce chemical LTD. Thus simultaneous presynaptic generation of cyclic GMP and inhibition of PKA is sufficient to induce LTD of synaptic transmission at Schaffer collateral-CA1 synapses.
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PMID:Chemically induced, activity-independent LTD elicited by simultaneous activation of PKG and inhibition of PKA. 1048 71

Phosphorylation of cyclic AMP response element binding protein (CREB) at amino acid serine 133 appears as an important link between the norepinephrine (NE)-induced activation of second messenger systems and the stimulation of melatonin biosynthesis. Here we investigated in the rat pineal gland: 1) the type of protein kinase that mediates CREB phosphorylation: and 2) its impact on melatonin biosynthesis. Immunochemical or immunocytochemical demonstration of serine133-phosphorylated cyclic AMP regulated element binding protein (pCREB) and radioimmunological detection of melatonin revealed that only cyclic AMP-dependent protein kinase (PKA) inhibitors suppressed NE-induced CREB phosphorylation and stimulation of melatonin biosynthesis, whereas inhibitors of cyclic GMP-dependent protein kinase (PKG), mitogen-activated protein kinase kinase, protein kinase C, or calcium-calmodulin-dependent protein kinase (CaMK) were ineffective. Investigations with cyclic AMP-agonist pairs that selectively activate either PKA type I or II link NE-induced CREB phosphorylation and stimulation of melatonin biosynthesis to the activation of PKA type II. Our data suggest that PKA type II plays an important role in the transcriptional control of melatonin biosynthesis in the rat pineal organ.
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PMID:CREB phosphorylation and melatonin biosynthesis in the rat pineal gland: involvement of cyclic AMP dependent protein kinase type II. 1053 67

Previously, we have demonstrated that excitotoxicity of oligodendrocyte-like cells (OLC), differentiated from immortalized rat O-2A progenitor cells (CG-4 cells), is prevented by cyclic AMP-elevating agents. We now report that some agents that elevate cyclic GMP prevent OLC excitotoxicity. Kainate-induced injury was prevented by cyclic GMP analogues (8-bromo-cyclic GMP and dibutyryl cyclic GMP), a guanylate cyclase activator [atrial natriuretic peptide (ANP)], and phosphodiesterase inhibitors [3-isobutyl-1-methylxanthine (IBMX), ibudilast, propentofylline, and rolipram]. When both forskolin and 8-bromo-cyclic GMP were added, kainate-induced injury was additively prevented. There was a strong positive correlation between suppression of kainate-induced Ca2+ influx and prevention of injury by these chemicals. The measurement of intracellular cyclic AMP and cyclic GMP by radioimmunoassay demonstrated the following: an increase of cyclic GMP with treatment with 8-bromo-cyclic GMP, dibutyryl cyclic GMP, and ANP; an increase of cyclic AMP with treatment with ibudilast and rolipram; and an increase of both cyclic AMP and cyclic GMP with treatment with IBMX and propentofylline. Kainate-induced Ca2+ influx was decreased by 8-(4-chlorophenylthiol)-guanosine-3',5'-monophosphate, an activator of cyclic GMP-dependent protein kinase (PKG), or okadaic acid, an inhibitor of protein phosphatases 1 and 2A. RT-PCR and westem blotting of OLC demonstrated transcription of PKG II gene and translation of PKG Ibeta mRNA, but no translation of PKG Ialpha mRNA. Therefore, we concluded that the cyclic GMP/PKG system prevents OLC excitotoxicity.
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PMID:Cyclic GMP/cyclic GMP-dependent protein kinase system prevents excitotoxicity in an immortalized oligodendroglial cell line. 1064 14

1. We tested the hypothesis that the negative functional effects of cyclic GMP (cGMP) oppose the positive effects of cyclic AMP (cAMP) in cardiac myocytes through interaction at the level of their respective protein kinases. 2. Cell shortening was studied using a video-edge detector. The O2 consumption of a suspension of rabbit ventricular myocytes was measured using O2 electrodes. Protein phosphorylation was measured autoradiographically following SDS-PAGE. Data were collected with: (1) 8-bromo-cGMP (8-Br-cGMP) 10(-7) or 10(-5) M; (2) 8-bromo-cAMP (8-Br-cAMP) 10(-7) or 10(-5) M; (3) 8-Br-cAMP 10(-5) M followed by 8-Br-cGMP 10(-7) or 10(-5) M; (4) 8-Br-cGMP 10(-5) M followed by 8-Br-cAMP 10(-7) or 10(-5) M; (5) 8-Br-cGMP 10(-7) or 10(-5) M followed by KT 5720 (cAMP-dependent protein kinase inhibitor) or KT 5823 (cGMP-dependent protein kinase inhibitor) 10(-6) M; and (6) 8-Br-cAMP 10(-7) or 10(-5) M followed by KT 5720 or KT 5823 10(-6) M. 3. 8-Br-cGMP 10(-5) M decreased percent shortening (Pcs) from 6.3+/-0.6 to 3.6+/-0.4% and rate of shortening (Rs) from 66.7+/-4.4 to 41.8+/-4.2 microm s(-1). 8-Br-cAMP 10(-5) M increased Pcs (from 3.7+/-0.2 to 4.8+/-0.2) and Rs (from 50.0+/-3.0 to 60.0+/-3.1). With 8-Br-cAMP 10(-5) M, 8-Br-cGMP 10(-5) M decreased Pcs and Rs less. The positive functional effects of 8-Br-cAMP 10(-7) or 10(-5) M were also diminished with 8-Br-cGMP 10(-5) M. Following 8-Br-cGMP 10(-7) or 10(-5) M, KT 5720 10(-6) M further decreased Pcs to 2.5+/-0.3 and Rs to 30.0+/-4.1. KT 5823 10(-6) M returned Pcs to 4.7+/-0.4 and Rs to 61.3+/-5.3. Following 8-Br-cAMP 10(-7) or 10(-5) M, KT 5720 decreased the elevated Pcs and Rs significantly and KT 5823 10(-6) M further increased these parameters. 4. cGMP and cAMP phosphorylated the same five protein bands. With KT 5720 or KT 5823, all of the bands were lighter at the same concentration of 8-Br-cAMP and 8-Br-cGMP. 5. We conclude that, in rabbit ventricular myocytes, the opposing functional effects of cGMP and cAMP are related to the interaction at the level of their respective protein kinases.
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PMID:Opposing functional effects of cyclic GMP and cyclic AMP may act through protein phosphorylation in rabbit cardiac myocytes. 1109 49


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