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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term potentiation (LTP) in the hippocampus has an early phase (E-LTP) that can be induced by one- or two-train tetanization, lasts approximately 1 hr, and is cAMP-dependent protein kinase (PKA) and protein synthesis independent and a late phase (L-LTP) that can be induced by three- or four-train tetanization, lasts >3 hr, and is reduced by inhibitors of PKA and of protein or RNA synthesis. Nitric oxide (NO) is thought to be involved in E-LTP, but until now there has been no information about the role of the NO-signaling pathway in L-LTP. We examined this question at the Schaffer collateral-CA1 synapses in slices of mouse hippocampus. An inhibitor of NO synthase blocked L-LTP induced by three-train tetanization and reduced L-LTP induced by four-train tetanization, whereas an inhibitor of PKA was more effective in blocking four-train L-LTP than three-train L-LTP. Three-train L-LTP was also blocked by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase (PKG). Conversely, either NO or cGMP analogs paired with one-train tetanization produced late-phase potentiation, and the cGMP-induced potentiation was blocked by inhibitors of protein or RNA synthesis and an inhibitor of PKG, but not by an inhibitor of PKA. To test a possible downstream target of PKG, we examined changes in phospho-CRE-binding protein (phospho-CREB) immunofluorescence in the CA1 cell body area and obtained results similar to those of the electrophysiology experiments. These results suggest that NO contributes to L-LTP by stimulating guanylyl cyclase and cGMP-dependent protein kinase, which acts in parallel with PKA to increase phosphorylation of the transcription factor CREB.
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PMID:Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. 1057 22

1. Intracellular calcium concentration ([Ca2+]i) was measured in mouse whole islets of Langerhans using the calcium-sensitive fluorescent dye Indo-1. 2. Application of physiological concentrations of 17beta-oestradiol in the presence of a stimulatory glucose concentration (8 mM) potentiated the [Ca2+]i signal in 83 % of islets tested. Potentiation was manifested as either an increase in the frequency or duration of [Ca2+]i oscillations. 3. The effects caused by 17beta-oestradiol were mimicked by the cyclic nucleotide analogues 8-bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP). 4. Direct measurements of both cyclic nucleotides demonstrated that nanomolar concentrations of 17beta-oestradiol in the presence of 8 mM glucose increased cGMP levels, yet cAMP levels were unchanged. The increment in cGMP was similar to that induced by 11 mM glucose. 5. Patch-clamp recording in intact cells showed that 8-Br-cGMP reproduced the inhibitory action of 17beta-oestradiol on ATP-sensitive K+ (KATP) channel activity. This was not a membrane-bound effect since it could not be observed in excised patches. 6. The action of 17beta-oestradiol on KATP channel activity was not modified by the specific inhibitor of soluble guanylate cyclase (sGC) LY 83583. This result indicates a likely involvement of a membrane guanylate cyclase (mGC). 7. The rapid decrease in KATP channel activity elicited by 17beta-oestradiol was greatly reduced using Rp-8-pCPT-cGMPS, a specific blocker of cGMP-dependent protein kinase (PKG). Conversely, Rp-cAMPS, which inhibits cAMP-dependent protein kinase (PKA), had little effect. 8. The results presented here indicate that rapid, non-genomic effects of 17beta-oestradiol after interaction with its binding site at the plasma membrane of pancreatic beta-cells is a cGMP-dependent phosphorylation process.
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PMID:Non-genomic actions of 17beta-oestradiol in mouse pancreatic beta-cells are mediated by a cGMP-dependent protein kinase. 1058 11

The effects of hypoxanthine and xanthine oxidase-induced superoxide anion were evaluated on various signal transduction pathways in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Superoxide increased inositol 1,4,5-tris-phosphate (IP(3)) formation in a concentration- and time-dependent manner in both strains but more markedly in SMCs from SHR. Various antioxidants significantly decreased the superoxide-induced IP(3) formation in both strains. In addition, tyrosine kinase inhibitors, genistein and tyrphostin A25, inhibited the superoxide-induced IP(3) formation more markedly in SHR than in WKY. Moreover, superoxide decreased the basal level of cGMP to a greater extent in SHR and also suppressed the rise in cGMP induced by S-nitroso-N-acetylpenicillamine. In addition, the superoxide-induced increase in IP(3) formation was significantly inhibited by guanylyl cyclase stimulator S-nitroso-N-acetylpenicillamine but was potentiated by ODQ (a guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one) and KT5823 (a cGMP-dependent protein kinase inhibitor), with a greater effect in SHR. Finally, the superoxide-enhanced IP(3) formation was not accompanied by simultaneous changes in cAMP levels, and inhibition of the adenylyl cyclase pathway did not modify the superoxide-induced IP(3) formation. Our results thus demonstrate a stimulatory effect of superoxide on IP(3) formation, mediated by the tyrosine kinase-coupled phospholipase C(gamma) activity, and an inhibitory effect of superoxide on cGMP formation in vascular SMCs. The increased reactivity of the phospholipase C pathway and the decreased cross inhibition of the IP(3) pathway by cGMP in the presence of superoxide may underlie the altered functions of vascular SMCs in SHR.
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PMID:Effects of superoxide on signaling pathways in smooth muscle cells from rats. 1060 Nov 26

We tested the hypothesis that protein kinase (PK)G activation in response to nitric oxide ((*)NO) mediates tumor necrosis factor (TNF)-alpha-induced activation of the transcription factor activating protein-1 (AP-1) in pulmonary microvessel endothelial monolayers (PEM). The DNA-binding activity of AP-1 was assessed using the electrophoretic mobility shift assay. TNF treatment (1,000 U/ml) for 4 h induced a significant increase in DNA binding of AP-1. The effects of TNF were prevented by the superoxide radical scavenger superoxide dismutase (SOD) (100 U/ml), the (*)NO synthase inhibitor aminoguanidine (100 microM), the guanylate cyclase inhibitor ODQ (100 microM), and the PKG inhibitors KT5823 (1 microM) and 8-bromo-cyclic guanosine monophosphate (cGMP)-thioate (100 microM). Spermine-NO (1 microM) and L-arginine (400 microM) prevented the aminoguanidine-induced ablation of AP-1 activation in response to TNF. Phosphorylation of H-Arg-Lys-Ile-Ser-Ala-Ser-Glu-Phe-Asp-Arg-Pro-Leu-Arg-OH (BPDEtide), a specific substrate for PKG, measured the activity of cGMP-dependent protein kinase (PKG). TNF for 0.5 h induced an increase in PKG activity that was prevented by aminoguanidine, ODQ, KT5823, and 8-bromo-cGMP-thioate; however, SOD had no effect. The PKG agonist 8-bromo-cGMP (100 microM), when given alone, increased PKG activity but induced significant DNA-binding activity of AP-1 only when given in the ODQ + TNF Group. SIN-1 (1 mM, a peroxynitrite agonist) increased DNA-binding activity of AP-1. SOD prevented SIN-1-induced AP-1 activation, a response similar to that of the SOD + TNF Group. PEM were transfected with the chloramphenicol acetyltransferase (CAT) reporter plasmid pBLCAT2, which contains a regulation sequence responsive to AP-1. The pharmacologic profile of TNF-induced CAT activity was identical to TNF-induced DNA binding by AP-1. Thus, TNF-induced AP-1-dependent gene transcription is modulated by (*)NO-dependent mediated activation of PKG.
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PMID:Tumor necrosis factor-alpha-induced activating protein-1 activity is modulated by nitric oxide-mediated protein kinase G activation. 1061 72

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

The GABA(A) receptor and the non-NMDA subtype of the ionotropic glutamate receptor were co-expressed in Xenopus oocytes by injection of quail brain mRNA. The oocytes were treated with various protein kinase (PK) and protein phosphatase (PP) activators and inhibitors and the effects on receptor functioning were monitored. Two phorbol esters, 4-beta-phorbol 12-myristate-13-acetate (PMA) and 4-beta-phorbol 12,13-dibutyrate (PDBu); the cGMP-dependent PK activators sodium nitroprusside (SNP) and S-nitrosoglutathione (SNOG); and the PP inhibitor okadaic acid (OA) reduced the amplitude of the GABA-induced currents, whilst the PK inhibitor staurosporine potentiated it. In addition, PMA, PDBu, SNP, and OA reduced the desensitization of the GABA-induced response. Identical treatments generally had similar but less pronounced effects on responses generated by kainate (KA) but the desensitization characteristic of the non-NMDA receptor was not affected. None of the treatments had any effect on the reversal potentials of the induced currents. Immunoblots revealed that the oocytes express endogenous PKG and guanylate cyclase. The results are discussed in terms of the molecular structures of GABA(A) and non-NMDA receptors and the potential functional consequences of phosphorylation/dephosphorylation.
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PMID:Protein kinase and phosphatase modulation of quail brain GABA(A) and non-NMDA receptors co-expressed in Xenopus oocytes. 1067 79

In this study, we highlight a role for the nitric oxide-cGMP-dependent protein kinase (NO-G-kinase) signaling pathway in glial intercellular Ca(2+) wave initiation and propagation. Addition of the NO donor molsidomine (100-500 microM) or puffing aqueous NO onto primary glial cell cultures evoked an increase in [Ca(2+)](i) in individual cells and also local intercellular Ca(2+) waves, which persisted after removal of extracellular Ca(2+). High concentrations of ryanodine (100-200 microM) and antagonists of the NO-G-kinase signaling pathway essentially abrogated the NO-induced increase in [Ca(2+)](i), indicating that NO mobilizes Ca(2+) from a ryanodine receptor-linked store, via the NO-G-kinase signaling pathway. Addition of 10 microM nicardipine to cells resulted in a slowing of the molsidomine-induced rise in [Ca(2+)](i), and inhibition of Mn(2+) quench of cytosolic fura-2 fluorescence mediated by a bolus application of 2 microM aqueous NO to cells, indicating that NO also induces Ca(2+) influx in glia. Mechanical stress of individual glial cells resulted in an increase in intracellular NO in target and neighboring cells and intercellular Ca(2+) waves, which were NO, cGMP, and G-kinase dependent, because incubating cells with nitric oxide synthase, guanylate cyclase, and G-kinase inhibitors, or NO scavengers, reduced Delta[Ca(2+)](i) and the rate of Ca(2+) wave propagation in these cultures. Results from this study suggest that NO-G-kinase signaling is coupled to Ca(2+) mobilization and influx in glial cells and that this pathway plays a fundamental role in the generation and propagation of intercellular Ca(2+) waves in glia.
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PMID:A fundamental role for the nitric oxide-G-kinase signaling pathway in mediating intercellular Ca(2+) waves in glia. 1068 78

Atrial natriuretic peptide (ANP) inhibits the proliferation of many cells, in part through interfering with signal transduction enacted by G protein-coupled growth factor receptors. Signaling interactions between ANP and the G protein-coupled growth factor receptor ligand, endothelin-3 (ET-3), regulate astrocyte proliferation at a very proximal but undefined point. Here, we find that ANP inhibits the ability of ET-3 to activate Galpha(q) and Galpha(i) in these cells. ANP stimulated the translocation of endogenous regulators of G protein-signaling (RGS) proteins 3 and 4 from the cytosol to the cell membrane, and enhanced their association with Galpha(q) and Galpha(i). ANP effects were significantly blocked by HS-142-1, an inhibitor of guanylate cyclase activation, or by ET-3. KT5823, an inhibitor of cyclic GMP-dependent protein kinase (PKG) reversed the RGS translocation induced by ANP; conversely, expression of an active catalytic subunit of PKG-I, or 8-bromo-cyclic GMP stimulated RGS translocation. ANP caused the phosphorylation of both RGS proteins in a PKG-dependent fashion, and the expressed PKG (in the absence of ANP) also stimulated RGS phosphorylation. A novel cross-talk between PKG and RGS proteins is stimulated by ANP and leads to the increased translocation and association of RGS proteins with Galpha. The rapid inactivation of G proteins provides a mechanism by which ANP inhibits downstream signaling to the cell proliferation program.
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PMID:Natriuretic peptides inhibit G protein activation. Mediation through cross-talk between cyclic GMP-dependent protein kinase and regulators of G protein-signaling proteins. 1070 9

The effects of the different types of soluble guanylate cyclase (sGC) stimulators on the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) in both human and rat platelets were studied under in vitro and in vivo conditions. sGC-dependent VASP phosphorylation (at Ser(239) and Ser(157)) both by the new direct sGC stimulator YC-1 and by NO donors was examined by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS/PAGE) with different antibodies. One antibody, which recognizes VASP independent of its phosphorylation state, was used to detect the mobility shift of VASP caused by Ser(157) phosphorylation. The other antibody was specifically directed against VASP phosphorylated at Ser(239), the cGMP-dependent protein kinase (PKG) preferred phosphorylation site of VASP. In vitro YC-1 increased both VASP phosphorylation and cyclic guanosine monophosphate (cGMP) levels as did the NO donors 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO) and sodium nitroprusside (SNP). The combination of both types induced a synergistic effect in both VASP phosphorylation and cGMP increase. In rat platelets, similar effects could be shown in vitro. In vivo we observed a significant increase in cGMP and a distinct effect on VASP phosphorylation in rat platelets 1 h after oral administration of YC-1. These biochemical alterations are supported by a significant prolongation in rat-tail bleeding time. Direct stimulators of sGC like YC-1 are on the one hand direct potent stimulators of the cGMP/PKG/VASP pathway in platelets and on the other hand synergize with NO, the physiologic stimulator of sGC. Therefore YC-1-like substances are interesting tools for the development of new cardiovascular drugs with vasodilatory and antithrombotic properties.
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PMID:The vasodilator-stimulated phosphoprotein (VASP): target of YC-1 and nitric oxide effects in human and rat platelets. 1071 Jan 23

Bone resorption by osteoclasts is modified by agents that affect cyclic guanosine monophosphate (cGMP), but their relative physiological roles, and what components of the process are present in osteoclasts or require accessory cells such as osteoblasts, are unclear. We studied cGMP regulation in avian osteoclasts, and in particular the roles of nitric oxide and natriuretic peptides, to clarify the mechanisms involved. C-type natriuretic peptide drives a membrane guanylate cyclase, and increased cGMP production in mixed bone cells. However, C-type natriuretic peptide did not increase cGMP in purified osteoclasts. By contrast, osteoclasts did produce cGMP in response to nitric oxide (NO) generators, sodium nitroprusside or 1-hydroxy-2-oxo-3,3-bis(3-aminoethyl)-1-triazene. These findings indicate that C-type natriuretic peptide and NO modulate cGMP in different types of bone cells. The activity of the osteoclast centers on HCI secretion that dissolves bone mineral, and both NO generators and hydrolysis-resistant cGMP analogues reduced bone degradation, while cGMP antagonists increased activity. NO synthase agonists did not affect activity, arguing against autocrine NO production. Osteoclasts express NO-activated guanylate cyclase and cGMP-dependent protein kinase (G-kinase). G-kinase reduced membrane HCI transport activity in a concentration-dependent manner, and phosphorylated a 60-kD osteoclast membrane protein, which immunoprecipitation showed is not an H+-ATPase subunit. We conclude that cGMP is a negative regulator of osteoclast activity. cGMP is produced in response to NO made by other cells, but not in response to C-type natriuretic peptide. G-kinase modulates osteoclast membrane HCI transport via intermediate protein(s) and may mediate cGMP effects in osteoclasts.
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PMID:Nitric oxide regulation of cGMP production in osteoclasts. 1073 42


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