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)

Despite interest in understanding glucagon-like peptide-1 (GLP-1) production, the factors important for GLP-1 biosynthesis remain poorly understood. We examined control of human proglucagon gene expression in NCI-H716 cells, a cell line that secretes GLP-1 in a regulated manner. Insulin, phorbol myristate acetate, or forskolin, known regulators of rodent proglucagon gene expression, had no effect, whereas sodium butyrate decreased levels of NCI-H716 proglucagon mRNA transcripts. The inhibitory effect of sodium butyrate was mimicked by trichostatin A but was not detected with sodium acetate or isobutyrate. The actions of butyrate were not diminished by the ERK1/2 inhibitor PD98059, p38 inhibitor SB203580, or soluble guanylate cyclase inhibitor LY83583 or following treatment of cells with KT5823, a selective inhibitor of cGMP-dependent protein kinase. NCI-H716 cells expressed multiple proglucagon gene transcription factors including isl-1, pax-6, pax-2, cdx-2/3, pax-4, hepatocyte nuclear factor (HNF)-3 alpha, HNF-3beta, HNF-3 gamma, and Nkx2.2. Nevertheless, the butyrate-dependent inhibition of proglucagon gene expression was not associated with coordinate changes in transcription factor expression and both the human and rat transfected proglucagon promoters were transcriptionally inactive in NCI-H716 cells. Hence, NCI-H716 cells may not be a physiologically optimal model for studies of human enteroendocrine proglucagon gene transcription.
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PMID:Aberrant regulation of human intestinal proglucagon gene expression in the NCI-H716 cell line. 1269 11

Insulin-degrading enzyme (IDE) is a metalloprotease implicated in insulin degradation and suggested to have a variety of additional functions, including the clearance of amyloid beta peptides of Alzheimer's disease. Little is known about endogenous proteins that may interact with and modulate IDE's activity in the cell. We purified and characterized two proteins from mouse leukemic splenocytes that interact with IDE and inhibit its insulin-degrading activity. A protein of 14 kDa was similar to a competitive IDE inhibitor reported previously. The major inhibitor was identified by amino acid sequencing as ubiquitin, a protein that is post-translationally covalently attached to other intracellular proteins and regulates diverse cellular processes. Ubiquitin inhibited insulin-degrading activity of IDE and diminished crosslinking of 125I-insulin to IDE in a specific, concentration-dependent, reversible, and ATP-independent manner. Ubiquitin did not affect the crosslinking of 125I-insulin to insulin receptors or of 125I-atrial natriuretic peptide (ANP) to its receptor guanylate cyclase-A. These findings suggest a novel role for ubiquitin or perhaps proteins with ubiquitin-like domains in regulating the function of IDE.
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PMID:Non-covalent interaction of ubiquitin with insulin-degrading enzyme. 1285 Feb 77

Treatment of rat islets with the cytokine IL-1 results in the inhibition of mitochondrial function and insulin secretion, events that are mediated by beta-cell expression of iNOS [inducible nitric oxide (NO) synthase] and production of NO. beta-Cells recover from the inhibitory actions of NO, produced following 24 h incubation with IL-1, on islet oxidative metabolism and insulin secretion if iNOS enzymatic activity is inhibited and the islets are cultured (in the presence of IL-1 and iNOS inhibitors) for a brief period of 8 h. Islet recovery from cytokine- and NO-mediated damage is an active process that requires new gene expression, and NO itself is one activator of this recovery process. In this study, the mechanism by which NO stimulates islet recovery has been examined. Incubation of rat islets or RINm5F cells with the NO donor compound, sodium (Z)-1(N,N-diethylamino) diazen-1-ium-1,2-diolate (DEA-NO) for 1 h results in a 60% inhibition of mitochondrial aconitase activity. beta-Cells completely recover aconitase activity if the cells are washed to remove the NO donor compound and incubated for an additional 5 h in the absence of DEA-NO. The recovery of mitochondrial aconitase activity correlates with a 4-fold increase in cyclic GMP accumulation and is prevented by the inhibition of guanylate cyclase. The recovery of aconitase activity also correlates with the activation of members of the MAPKs, p38, c-Jun N-terminal kinase (JNK) and ERK, and the activation p38 and JNK is attenuated by inhibition of guanylate cyclase. ERK and p38 do not appear to participate in the recovery process as selective inhibition of these kinases fails to prevent recovery of aconitase activity; however, transduction of beta-cells with a dominant negative mutant JNK prevents beta-cell recovery from NO-mediated damage. These findings support a role for guanylate cyclase and JNK in the recovery of beta-cells from NO-mediated damage.
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PMID:Role for c-Jun N-terminal kinase in beta-cell recovery from nitric oxide-mediated damage. 1286 20

Hippocampal neuron survival/growth and gene expression have been examined after prenatal (in utero) exposure of rats to EGb 761, a leaf extract of Ginkgo biloba. Oral administration of EGb 761 (100 or 300 mg/kg/day) to pregnant dams for 5 days increased the number of hippocampal neurons (maintained in culture) of their fetuses, indicating a neurotrophic effect of the extract. Using large-scale oligonucleotide microarrays containing over 8000 combined rat genes and expressed sequence tag clusters, it was shown that treatment of pregnant dams with EGb 761 (25, 50 or 100 mg/kg/day for 5 days) altered the expression of 187 genes in the hippocampi of male fetuses and 160 genes in those of female fetuses. Using gene-cluster analysis, these genes were grouped into 18 distinct clusters for males and 17 distinct clusters for females. Among these clusters, 35 genes shared a common expression pattern in male and female hippocampal development. Of these genes, the changes observed in insulin growth factor II, insulin growth factor binding protein 2, testosterone repressed prostate message-2, glutathione-dependent dehydroascorbate reductase, lipoprotein lipase, guanylate cyclase and DNA binding protein Brn-2 were confirmed by real-time quantitative polymerase chain reaction. These findings, which have provided the first genetic profile of the effects of EGb 761 on the developing rat hippocampus, increase our understanding of the molecular and genetic programs that are activated by the extract. These effects of EGb 761 may underlie its neuroprotective properties.
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PMID:Prenatal exposure of rats to Ginkgo biloba extract (EGb 761) increases neuronal survival/growth and alters gene expression in the developing fetal hippocampus. 1293 14

Insulin resistance is associated with vascular disease. Physiological concentrations of insulin inhibit cultured vascular smooth muscle cell (VSMC) contraction and migration by increasing nitric oxide (NO)-stimulated cGMP accumulation. The failure to do so in insulin-resistant states may aggravate vascular disease. We sought to determine the mechanism of insulin's increase in cGMP accumulation. Isobutylmethylxanthine, an inhibitor of phosphodiesterase activity, inhibited the decline in cGMP levels measured by immunoassay in cGMP-loaded cultured rat aortic VSMCs, but 1 nmol insulin did not. Thus, insulin's increase in cGMP accumulation is due to stimulated production, not inhibited hydrolysis and/or efflux. Insulin, which increases the NADH/NAD+ ratio in these cells, stimulated superoxide anion (O2-) accumulation measured by lucigenin luminescence to 256+/-25% (P<0.05) by a process that was blocked by the NADH oxidase inhibitor diphenyliodonium (DPI) and enhanced by the superoxide dismutase inhibitor diethyldithiocarbonate (DETCA). Insulin also stimulated hydrogen peroxide (H2O2) accumulation measured by horseradish peroxidase/luminol luminescence to 221+/-22% (P<0.05) by a DETCA-sensitive mechanism. H2O2 (100 micromol/L) in the absence of insulin increased NO-stimulated cGMP accumulation to 151+/-11% (P<0.05). Insulin alone increased NO-stimulated cGMP accumulation to 183+/-17% (P<0.05), and this was blocked by either DPI or DETCA. We conclude that insulin increases NADH oxidase-derived O2- production in cultured rat VSMCs. This did not cause the expected scavenging of NO resulting in the reduction of NO-stimulated guanylate cyclase activity, but enough O2- was metabolized to H2O2 to increase overall NO-stimulated cGMP production.
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PMID:Insulin-stimulated hydrogen peroxide increases guanylate cyclase activity in vascular smooth muscle. 1296 80

Insulin and insulin-like growth factor I (IGF-I) both play important roles in vascular remodeling. Moreover, nitric oxide (NO) is well established as a counterregulatory agent that opposes the actions of several vascular agonists, in part by decreasing smooth muscle motility. We tested the hypothesis that NO blocks insulin or IGF-I-induced rat aortic smooth muscle cell motility via a mechanism involving the attenuation of agonist-induced elevation of hydrogen peroxide levels and cGMP as mediator. Insulin or IGF-I induced an increase of hydrogen peroxide levels and cell motility. Both effects were blocked by catalase or diphenyleneiodonium, indicating that hydrogen peroxide elevation is necessary for induction of cell motility. Two NO donors mimicked the effects of catalase, indicating that NO decreases cell motility by suppressing agonist-induced elevation of hydrogen peroxide. A cGMP analogue mimicked the effect of NO, whereas a guanyl cyclase inhibitor blocked the effect of NO on hydrogen peroxide levels, indicating that elevation of cGMP is both necessary and sufficient to account for the reduction of hydrogen peroxide levels. A NO donor as well as a cGMP analogue attenuated insulin-stimulated NADPH activity, indicating that NO decreases hydrogen peroxide levels by inhibiting the generation of superoxide, via a cGMP-mediated mechanism. Finally, exogenous hydrogen peroxide increased cell motility and reversed the inhibitory effect of cGMP. These results support the view that NO plays an antioxidant role via reduction of hydrogen peroxide in cultured rat aortic smooth muscle cells and that this effect is both necessary and sufficient to account for its capacity to decrease cell motility.
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PMID:Nitric oxide attenuates insulin- or IGF-I-stimulated aortic smooth muscle cell motility by decreasing H2O2 levels: essential role of cGMP. 1475 55

Sodium nitroprusside (SNP), a nitric oxide (NO.) donor, stimulates glucose uptake in skeletal muscle. We investigated the stimulatory effect of SNP on glucose uptake in cardiomyocytes and the possible role of soluble guanylate cyclase, phosphatidylinositol-3-kinase (PI-3-kinase) and the mitogen-activated protein kinases (MAPKs). Cardiomyocytes were isolated from adult male Wistar rats by trypsin/collagenase perfusion and glucose uptake determined from the accumulation of 3H-2-deoxyglucose. SNP caused a dose-dependent increase in glucose uptake with 200-300% increase at 30 mM. Cytochalasin B completely prevented the SNP-induced increase in glucose uptake. 8-Br-cGMP (100 microM) and the NO. donor spermineNONOate (100 microM) were without effect on basal glucose uptake. SNP-stimulated glucose uptake was not inhibited by the guanylate cyclase inhibitor ODQ (10 microM). Sodium ferrocyanide (Na4Fe(CN)6), a compound structurally related to SNP, but without any NO. group, also stimulated glucose uptake in cardiomyocytes suggesting that the effect of SNP could be unrelated to liberation of NO. Wortmannin, an inhibitor of PI-3-kinase, inhibited insulin-stimulated glucose uptake completely but did not affect SNP-stimulated glucose uptake. SNP-stimulated glucose uptake was inhibited by 50 microM PD 098059 (inhibitor of the MAPK-kinases that activate external regulated kinase [ERK1/2]) and by 50 microM SB203580 (inhibitor of p38MAPK). In conclusion, high SNP concentrations dose-dependently stimulate glucose uptake in cardiomyocytes and our data suggest a role for MAPK signalling, but not PI-3-kinase and soluble guanylate cyclase, in stimulation of glucose uptake.
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PMID:Evidence that nitroprusside stimulates glucose uptake in isolated rat cardiomyocytes via mitogen-activated protein kinase. 1497 46

Biochemical modifications associated with the increase in platelet activity with age are not well defined. Furthermore it is well known that the nitric oxide/cyclic 3', 5'-guanosine monophosphate (cGMP) pathway regulates platelet aggregation. The aim of the present study was to examine the relationship between platelet content of cGMP and age. 120 normal subjects, evaluating the cGMP platelet concentration, 17betaE2, IGF-I, dehydroepiandrosterone sulphate (DHEAS), insulin, plasma glucose, lipid pattern, homocysteine and PAI-I antigen, were studied. The multivariate analysis in a model with cGMP as dependent variable and with age, LDL, apolipoprotein B (ApoB), DHEAS, E2 and insulin-like growth factor (IGF)-I as independent variables shows a negative correlation between cGMP and age (p<0.01, beta=-0.388). In conclusion our data suggest that the reduced efficiency of the system constitutive nitric oxide synthase (cNOS)/guanylate cyclase represents at least one of the reasons of the increased platelet aggregability with age.
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PMID:Platelet cGMP inversely correlates with age in healthy subjects. 1512 1

ATP-sensitive potassium (K(ATP)) channels regulate insulin release, vascular tone, and neuronal excitability. Whether these channels are modulated by NO, a membrane-permeant messenger in various physiological and pathological processes, is not known. The possibility of NO signaling via K(ATP) channel modulation is of interest because both NO and K(ATP) have been implicated in physiological functions such as vasodilation and neuroprotection. In this report, we demonstrate a mechanism that leads to K(ATP) activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring K(ATP) single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found K(ATP) stimulation by NO donor Noc-18, a specific NO effect abolished by NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) but not guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). NO stimulation of K(ATP) is indirect and requires Ras and mitogen-activated protein kinase kinase activities. Blockade of Ras activation by pharmacological means or by coexpressing either a dominant-negative or an S-nitrosylation-site mutant Ras protein significantly abrogates the effects of NO. Inhibition of mitogen-activated protein kinase kinase abolishes the NO activation of K(ATP) but suppression of phosphatidylinositol 3-kinase does not. The NO precursor l-Arg also stimulates K(ATP) via endogenous NO synthase and the Ras signaling pathway. In addition, in rat hippocampal neurons, the protective effect of ischemic preconditioning induced by oxygen-glucose deprivation requires K(ATP) and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by K(ATP) stimulation.
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PMID:NO stimulation of ATP-sensitive potassium channels: Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection. 1513 49

Nitric oxide (NO) is involved in adipose tissue biology by influencing adipogenesis, insulin-stimulated glucose uptake, and lipolysis. The enzymes responsible for NO formation in adipose cells are endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), whereas neuronal NO synthase (bNOS) is not expressed in adipocytes. We characterized the expression pattern and the influence of adipogenesis, obesity, and weight loss on genes belonging to the NO system in human subcutaneous adipose cells by combining in vivo and in vitro studies. Expression of most of the genes known to belong to the NO system (eNOS, iNOS, subunits of the soluble guanylate cyclase, and both genes encoding cGMP-dependent protein kinases) in human adipose tissue and isolated human adipocytes was detected. In vitro adipogenic differentiation increased the expression level of iNOS significantly, whereas eNOS expression levels were not influenced. The genes encoding eNOS, iNOS, and cGMP-dependent protein kinase 1 were expressed at higher levels in obese women. Expression of these genes, however, was not influenced by 5% weight loss. Insulin and angiotensin II (Ang II) increased NO production by human preadipocytes in vitro. Increased eNOS and iNOS expression in adipocytes and local effects of insulin and Ang II may increase adipose tissue production of NO in obesity.
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PMID:Regulation of the nitric oxide system in human adipose tissue. 1523 49


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