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

---

Query: EC:2.7.11.12 (PKG)
2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies indicate that cGMP is involved in long-term potentiation (LTP). However, the effects of application of tetanus to induce LTP on cGMP content and the mechanisms by which cGMP may modulate LTP have not been reported. The aim of this work was to study the time course of the changes in cGMP content and of the activity of soluble guanylate cyclase (sGC) (the enzyme that synthesizes cGMP) during LTP. Moreover, we also studied how the changes in cGMP affect cGMP-dependent protein kinase (PKG) and cGMP-degrading phosphodiesterase and the possible role of these changes in LTP. Application of tetanus induced a rise in cGMP, reaching a maximum 10 sec after tetanus. cGMP content decreased below basal levels 5 min after tetanus and remained decreased after 60 min. Activity of sGC increased 5 min after tetanus and returned to basal at 60 min. Tetanus increased the activity of cGMP-degrading phosphodiesterase at 5 and 60 min. GMP, the product of degradation, was increased at 5 and 60 min. Activation of phosphodiesterase and a decrease in cGMP were prevented by inhibiting PKG with Rp-8-bromoguanosine-cGMPS (Rp-8-Br-cGMPS). Inhibition of sGC [with ODQ (oxadiazolo quinoxalin-1-one) or NS 2028 (4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one)], of PKG (with Rp-8-Br-cGMPS), or of cGMP-degrading phosphodiesterase [with zaprinast or MBAM (4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline) ] impairs LTP. The results indicate that induction of LTP involves transient activation of sGC and an increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content.
...
PMID:Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. 1245 Nov 12

We have previously reported that cyclic guanosine-3',5'-monophosphate (cGMP) protects spinal motor neurons against acute reactive oxygen species (ROS)-induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced toxicity. In this study, we investigated the effects of phosphodiesterase (PDE) inhibitors on the survival of cultured spinal motor neurons. Selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) as well as a nonselective PDE inhibitor (aminophylline) protected motor and nonmotor neurons against both acute ROS-induced and chronic Glu-induced neurotoxicity, whereas selective inhibitors of PDE1-4 offered no protection. 8-Bromo-cGMP (8br-cGMP), a cGMP analogue, protected both motor and nonmotor neurons against acute ROS-induced toxicity but protected only nonmotor neurons against chronic Glu-induced toxicity. This neuroprotection was blocked by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Immunohistochemical staining confirmed that PDE5 and PKG are located in almost all rat lumbar spinal neurons. Furthermore, semiquantitative analysis of the immunostaining intensity revealed that PDE5 was more abundant in motor neurons than in nonmotor neurons. Our results suggest that this difference in the amount of PDE5 may be responsible for the vulnerability of motor neurons to chronic excitotoxicity. In addition, the results of this study raise the possibility that PDE5 inhibitors might be used as a treatment for amyotrophic lateral sclerosis.
...
PMID:Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons. 1254 4

Data suggest both presynaptic and postsynaptic changes contribute to activity-dependent long-term synaptic plasticity. We have shown that pairing elevation of intracellular [cyclic GMP], using the type V phosphodiesterase inhibitor zaprinast, with inhibition of cyclic AMP-dependent protein kinase (PKA), is sufficient to elicit chemical long-term depression (CLTD) of synaptic transmission at Schaffer collateral-CA1 and mossy fibre-CA3 synapses in rat hippocampus. CLTD does not require synaptic activity, and selective postsynaptic drug injections do not affect it, suggesting it is presynaptically induced and expressed. To directly evaluate this hypothesis, we tested whether CLTD of transmitter release can be expressed in isolated presynaptic nerve terminals. Presynaptic nerve terminals (synaptosomes) were isolated from rat hippocampi by Percoll density gradient centrifugation. Synaptosomes were loaded with [3H]glutamate, and basal and depolarisation-induced release of [3H]glutamate measured in control medium versus medium containing zaprinast (20 microm) plus or minus the PKA inhibitor H-89 (10 microm). Zaprinast produced a significant decrease in basal [3H]glutamate release. However, only combining zaprinast with H-89 significantly depressed K+-evoked [3H]glutamate release. After a 20-min drug washout, basal release returned to normal in all conditions, but K+-evoked [3H]glutamate release was persistently reduced only by the combination of zaprinast plus H-89. Long-term reduction of [3H]glutamate release from synaptosomes was completely prevented by the PKG inhibitor KT5823 (5 microm). These data demonstrate the existence of a presynaptic, cyclic GMP-PKG dependent cascade capable of expressing LTD of glutamate release from isolated hippocampal nerve terminals.
...
PMID:Pairing elevation of [cyclic GMP] with inhibition of PKA produces long-term depression of glutamate release from isolated rat hippocampal presynaptic terminals. 1260 82

(1) Cyclic GMP (cGMP) has been shown to be an important modulator of cardiac contractile function. A major component of cGMP regulation of contractility is cGMP-mediated inhibition of the cardiac calcium current (I(Ca)). An under-appreciated aspect of cyclic nucleotide signalling is hydrolysis of the cyclic nucleotide (i.e., breakdown by phosphodiesterases (PDEs)). The role of cGMP hydrolysis in regulating I(Ca) has not been studied. Thus the purpose of this study was to investigate if inhibition of cGMP hydrolysis can modulate I(Ca) in isolated guinea-pig ventricular myocytes. (2) Zaprinast, a selective inhibitor of cGMP-specific PDE (PDE5), caused a significant increase in cGMP levels in myocytes, but was without affect on basal or beta-adrenergic stimulated cAMP levels (consistent with its actions as a specific inhibitor of PDE5). (3) Zaprinast inhibited I(Ca) that was pre-stimulated with cAMP elevating agents (isoproterenol, a beta-adrenergic agonist; or forskolin, a direct activator of adenylate cyclase). The effect of zaprinast was greatly reduced by KT5823, an inhibitor of cGMP-dependent protein kinase (PKG). (4) Zaprinast also significantly inhibited basal I(Ca) when perforated-patch or whole-cell recording with physiological pipette calcium concentration (10(-7) M) was used. However, this effect was not observed when using standard calcium-free whole-cell recording conditions. (5) These results indicate that inhibition of cGMP hydrolysis can decrease both basal and cAMP-stimulated I(Ca). Thus, cGMP hydrolysis may likely be an important step for physiological modulation of I(Ca). This regulation may also be important in disease states in which cGMP production is increased and PDE5 expression is altered, such as heart failure.
...
PMID:Inhibition of cyclic GMP hydrolysis with zaprinast reduces basal and cyclic AMP-elevated L-type calcium current in guinea-pig ventricular myocytes. 1264 1

For deciphering the cyclic guanosine monophosphate (cGMP) signaling pathway, we employed chemical proteomics to identify the novel target molecules of cGMP. We used cGMP that was immobilized onto agarose beads with linkers directed at three different positions of cGMP. We performed a pull-down assay using the beads as baits on tissue lysates and identified 9 proteins by MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight) mass spectrometry. Some of the identified proteins were previously known cGMP targets, including cGMP-dependent protein kinase and cGMP-stimulated phosphodiesterase. Surprisingly, some of the coprecipitated proteins were never formerly reported to associate with the cGMP signaling pathway. The competition binding assays showed that the interactions are not by nonspecific binding to either the linker or bead itself, but by specific binding to cGMP. Furthermore, we observed that the interactions are highly specific to cGMP against other nucleotides, such as cyclic adenosine monophosphate (cAMP) and 5\'-GMP, which are structurally similar to cGMP. As one of the identified targets, MAPK1 was confirmed by immunoblotting with an anti-MAPK1 antibody. For further proof, we observed that the membrane-permeable cGMP (8-bromo cyclic GMP) stimulated mitogen-activated protein kinase 1 signaling in the treated cells. Our present study suggests that chemical proteomics can be a very useful and powerful technique for identifying the target proteins of small bioactive molecules.
...
PMID:Identification of novel target proteins of cyclic GMP signaling pathways using chemical proteomics. 1278 86

(1) Sildenafil (viagra) is a potent PDE5 inhibitor and thus a relaxant drug in corpus carvernosum smooth muscle. In the present work, we evidenced the presence of PDE5 isozyme and investigated the effect of sildenafil on the specific cyclic nucleotide phosphodiesterase (PDE) activity, smooth muscle tone and calcium signaling in the rat main pulmonary artery (MPA). (2) The PDE activity was measured in cytosolic and microsomal fractions. Total cAMP and cGMP-PDE activities were mainly present in the cytosolic fraction. Sildenafil (0.1 micro M) reduced by 72% cGMP-PDE activity, whereas zaprinast (10 micro M), a relatively selective PDE5 inhibitor, reduced this activity by 63%. Sildenafil (0.1 micro M) also inhibited significantly (22%) the cAMP-PDE activity. (3) Western blot analysis revealed the expression of PDE5 mainly in the cytosolic fraction of MPA. Sildenafil concentration-dependently inhibited (IC(50)=3.4 nM) the activity of MPA PDE5 partially purified by HPLC. (4) Sildenafil (0.1 nM-50 micro M) concentration-dependently relaxed MPA rings precontracted with phenylephrine (0.5 micro M). The potency of sildenafil (IC(50)=11 nM) was similar to that of a nitric oxide donor, sodium nitroprusside, but higher than that of zaprinast (IC(50)=600 nM). The vasorelaxant effect of sildenafil was not altered by endothelium removal or in the presence of KT 5823 (1 micro M) and H89 (1 micro M), potent inhibitors of PKG and PKA, respectively. (5) In isolated MPA myocytes, which had been loaded with the calcium fluorophore indo-1, sildenafil (10-100 nM) antagonized ATP- and endothelin-1-induced calcium oscillations but had no effect on the transient caffeine-induced [Ca(2+)](i) response. (6) This study demonstrates the presence of a functional and highly sildenafil-sensitive PDE5 isozyme in rat MPA. Inhibition of this isozyme mainly accounts for the potent pulmonary vasodilator action of sildenafil, which involves alteration in the inositol triphosphate-mediated calcium signaling pathway.
...
PMID:Effect of sildenafil on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery. 1278 11

The nitric oxide (NO)-cGMP pathway has been implicated as playing a crucial role in the induction of cerebellar long-term depression (LTD). The amplitude and duration of the cGMP signal is controlled by cyclic nucleotide phosphodiesterases (PDEs). Here we identify PDE5 and PDE1B as the two major cGMP-hydrolyzing PDEs specifically and differentially expressed in the Purkinje neurons of mouse cerebellum. PDE5 was found in all Purkinje neurons, whereas PDE1B was detected only in a subset of these cells, suggesting that individual Purkinje cells may differentially regulate cGMP, depending on the PDE isozymes expressed. Although expression of guanylate cyclase and/or cGMP-dependent protein kinase (PKG) in Purkinje cells have been reported, neither cGMP accumulation nor PKG activation in these cells in vivo has been demonstrated. To determine if changes in PKG activation and PDE5 regulation occur in vivo we have examined the phosphorylation of PDE5 in mouse cerebellar Purkinje cells by immunocytochemistry and Western blot analyses using a phosphospecific PDE5 antibody. Injection of sodium nitroprusside or selective PKG activators into the lateral ventricle of mouse brain induced PDE5 phosphorylation in vivo, but was completely missing in Purkinje cell-specific PKG I knock-out mice. In cerebellar slices, treatment with sildenafil or IBMX led to different levels of phospho-PDE5 accumulation and activation of PDE5. These results suggest that phosphorylation of PDE5 in Purkinje neurons after cGMP-PKG activation performs a critical role in the termination of the cGMP signal during LTD progression; moreover, PDE5 phosphorylation may be used as an in vivo indicator for PKG activation.
...
PMID:Individual cerebellar Purkinje cells express different cGMP phosphodiesterases (PDEs): in vivo phosphorylation of cGMP-specific PDE (PDE5) as an indicator of cGMP-dependent protein kinase (PKG) activation. 1287 85

Atherosclerosis involves cellular immune responses and altered vascular smooth muscle cell (VSMC) function. Nitric oxide (NO)/cGMP is uniquely capable of inhibiting key processes in atherosclerosis. In this study, we determined the effects of NO/cGMP and their molecular mechanisms in the regulation of NF-kappaB-dependent gene expression in VSMCs. We found that cGMP-elevating agents such as the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and C-type natriuretic peptide (CNP), reduced TNF-alpha-induced NF-kappaB-dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-kappaB are mediated by cAMP-dependent protein kinase (PKA) but not cGMP-dependent protein kinase (PKG) based on the findings that the selective PKA inhibitor, PKI, abolished the effects of SNAP and CNP on NF-kappaB, whereas the PKG inhibitor Rp-8-Br-PET-cGMP had no effect. Inhibition of cGMP-inhibited cAMP-hydrolyzing phosphodiesterase 3 (PDE3) blocked SNAP- and CNP-elicited effects on NF-kappaB-dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-kappaB-mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-alpha-induced NF-kappaB-dependent reporter gene expression but also reduced endogenous NF-kappaB-dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-kappaB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs.
...
PMID:Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. 1291 48

Ethanol exposure in airway epithelium increases cyclic AMP (cAMP)-dependent protein kinase (PKA) activity. Activation of PKA and cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) has been shown to increase ciliary beat frequency (CBF) in bovine bronchial epithelial cells (BBECs). We have shown that biologically relevant concentrations of ethanol stimulate increases in CBF in a nitric oxide-dependent manner, mediated through elevated cAMP levels and subsequent PKA activation. This ethanol-driven rapid and transient increase in CBF occurs 15 to 30 min after exposure to 100 mM ethanol. However, after prolonged exposure to 100 mM ethanol (>/=6 h), CBF and the catalytic activity of PKA return to baseline levels. We hypothesize that cyclic nucleotide-dependent phosphodiesterase (PDE) activity attenuates the duration of ethanol-stimulated ciliary motility. The effect of ethanol on the PDE activity in BBECs was determined through direct assay of catalytic activity. When BBECs were incubated with 100 mM ethanol, significant increases in cAMP levels occurred within 1 h, with corresponding increases in PKA activity. Treatment of BBECs with 100 mM ethanol increased cAMP-PDE activity significantly by 4 h. 3-Isobutyl-1-methylxanthine, Ro 20-1724, and rolipram inhibited ethanol-stimulated cAMP-PDE activity. These agents inhibited ethanol-stimulated cAMP-PDE activity and increased the magnitude of ethanol-stimulated PKA activity observed under the same conditions. These findings support the idea that acute exposure (<6 h) to ethanol increases cAMP levels, and the associated increase in PKA activation is regulated by cAMP-dependent PDE, specifically PDE4. Other compensatory mechanisms however, may be responsible for the down-regulation of PKA, which occurs after chronic epithelial exposure (>/=6 h) to ethanol.
...
PMID:Ethanol increases phosphodiesterase 4 activity in bovine bronchial epithelial cells. 1461 9

This study investigates the effect of protein kinase G (PKG) activation upon proliferation of human cultured prostatic stromal cells. The PKG II activator (8-pCPT-cGMP; IC50 of 113+/-42 nM) and the phosphodiesterase inhibitor, zaprinast (up to 50 microM), but not the PKG I isoform activators (APT-cGMP and PET-cGMP), reduced foetal calf serum-stimulated proliferation. The effect of 8-pCPT-cGMP (30 microM) was blocked by Rp-8-Br-cGMPS (5 microM) and Rp-8-pCPT-cGMP (5 microM), but not Rp-cAMPS (5 microM). 8-pCPT-cGMP (30 microM) and zaprinast (50 microM), but not PET-cGMP (30 microM), caused a significant increase in atypical nuclei and an increase in annexin-V staining. These data indicate that activation of PKG II induces apoptosis of human cultured prostatic stromal cells.
...
PMID:Protein kinase G II-mediated proliferative effects in human cultured prostatic stromal cells. 1463 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---