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)

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of catecholamines. In a previous report we found that intracerebroventricular administration of nitric oxide (NO) generator sodium nitroprusside (SNP) to conscious male rats inhibited dose-dependently the TH activity of the median eminence (ME). In the present study we have tested the in vitro effects of SNP on TH activity, its possible mediator and action mechanism. Exposure of the ME TH to SNP (50, 100 and 500 microM) caused concentration-dependent inhibition of its enzyme activity. Addition of; reduced hemoglobin Hb (10 microM), a NO scavenger, superoxide dismutase SOD (1000 units/ml), a superoxide scavenger enzyme, or uric acid UA (300 microM), a peroxynitrite scavenger, did not affect the enzyme activity by themselves, but prevented the inhibitory effect of SNP 500 microM. However, the presence of methylene blue MB (100 microM), a guanylyl cyclase inhibitor, did not alter either basal enzyme activity or the inhibitory action of SNP 500 microM. These results suggest that this action of SNP on TH of the ME would be mediated by peroxynitrite generated by the reaction of NO with superoxide.
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PMID:Nitric oxide inhibits tyrosine hydroxylase of rat median eminence. 1107 70

The core of adenylate and guanylate cyclases is formed by an intramolecular or intermolecular dimer of two cyclase domains arranged in an antiparallel fashion. Metazoan membrane-bound adenylate cyclases are composed of 12 transmembrane spanning regions, and two cyclase domains which function as a heterodimer and are activated by G-proteins. In contrast, membrane-bound guanylate cyclases have only one transmembrane spanning region and one cyclase domain, and are activated by extracellular ligands to form a homodimer. In the cellular slime mould, Dictyostelium discoideum, membrane-bound guanylate cyclase activity is induced after cAMP stimulation; a G-protein-coupled cAMP receptor and G-proteins are essential for this activation. We have cloned a Dictyostelium gene, DdGCA, encoding a protein with 12 transmembrane spanning regions and two cyclase domains. Sequence alignment demonstrates that the two cyclase domains are transposed, relative to these domains in adenylate cyclases. DdGCA expressed in Dictyostelium exhibits high guanylate cyclase activity and no detectable adenylate cyclase activity. Deletion of the gene indicates that DdGCA is not essential for chemotaxis or osmo-regulation. The knock-out strain still exhibits substantial guanylate cyclase activity, demonstrating that Dictyostelium contains at least one other guanylate cyclase.
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PMID:Guanylate cyclase in Dictyostelium discoideum with the topology of mammalian adenylate cyclase. 1123 75

The purpose of this study was to determine the effects of sodium nitroprusside (SNP), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (DETA/NO) and 3-morpholinosydnonimine (SIN-1), NO donors which yield different NO reactive species (NO+, NO* and peroxynitrite, respectively), as well as exogenous peroxynitrite, on gall bladder contractility. Under resting tone conditions, SNP induced a dose-dependent contraction with a maximal effect (10.3 +/- 0.7 mN, S.E.M.) at 1 mM. Consistent with these findings, SNP caused a concentration-dependent depolarization of gall bladder smooth muscle. The excitatory effects of SNP were dependent on extracellular calcium entry through L-type Ca2+ channels. Furthermore, the contraction and depolarization were sensitive to tyrosine kinase blockade, and an associated increase in tyrosine phosphorylation was detected in Western blot studies. DETA/NO induced dose-dependent relaxing effects. These relaxations were sensitive to the guanylyl cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one (ODQ, 2 microM) but they were not altered by treatment with the potassium channel blockers tetraethylammoniun (TEA, 5 mM) and 4-aminopyridine (4-AP, 5 mM). When tested in a reducing environment (created by 2.5 mM 1,4-dithiothreitol, DTT), SNP caused a relaxation of gall bladder muscle strips. Similarly, the SNP-induced contraction was converted to a relaxation, and associated hyperpolarization, when DTT was added during the steady state of an SNP-induced response. SIN-1 (0.1 mM), which has been shown to release peroxynitrite, induced relaxing effects that were enhanced by superoxide dismutase (SOD, 50 U ml(-1)). The relaxations induced by either SIN-1 alone or SIN-1 in the presence of SOD were strengthened by catalase (1000 U ml(-1)) and abolished by ODQ pretreatment. However, exogenous peroxynitrite induced a concentration-dependent contraction, which was dependent on activation of leukotriene (LT) metabolism and extracellular calcium. The peroxynitrite-induced contraction was abolished in the presence of the peroxynitrite scavenger melatonin. These results suggest that SIN-1 behaves as an NO* rather than a peroxynitrite source. We conclude that, depending on the redox state, NO has opposing effects on the motility of the gall bladder, being a relaxing agent when in NO * form and a contracting agent when in NO+ or peroxynitrite redox species form. Knowledge of the contrasting effects of the different redox forms of NO can clarify our understanding of the effects of NO donors on gall bladder and other smooth muscle cell types.
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PMID:A redox-based mechanism for the contractile and relaxing effects of NO in the guinea-pig gall bladder. 1131 47

In isolated coronary arteries, hypoxia induces an increase in tone by releasing an unidentified endothelium-derived contracting factor (EDCF). Isometric force was measured in an isolated rabbit coronary artery ring at 37 degrees C in control and high K+ (40 mM) pre-contracted conditions. Hypoxia (15 mmHg pO2) induced by equilibrating the perfusate with nitrogen. Hypoxia did not affect the resting tone but induced an endothelium-dependent contraction on pre-contracted rings. Inhibitors of nitric oxide (NO) were tested, L-NAME (10(-4) M) totally and L-NMMA (10(-4) M) partially convert the hypoxic contraction to an hypoxic relaxation. The addition of L-arginine (10(-4) or 10(-3) M) did not restore the response. Methylene blue (10( -5) M) and ODQ (1 H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one, 10(-5) M), both inhibitors of guanylate cyclase, also changed the hypoxic contraction into a hypoxic relaxation. Catalase (1200 U/ml), which decomposes hydrogen peroxide (H2O2), and superoxide dismutase (150 U/ml, SOD), a free radical scavenger, did not change the hypoxic response but quinacrine (50 microM), an inhibitor of phospholipase A2, significantly decreased it. Inhibitors of arachidonic acid metabolism (indomethacin, diethylcarbamazine, miconazole) however did not affect the hypoxic response. We conclude that in K+ pre-contracted rabbit coronary artery rings, hypoxia induces a contraction which is nitric oxide and arachidonic acid dependent.
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PMID:Possible role of nitric oxide and arachidonic acid pathways in hypoxia-induced contraction of rabbit coronary artery rings. 1147 Oct 68

Superoxide plays a role in blood pressure regulation in certain vascular diseases, however, its involvement in regulating basal blood pressure is uncertain. Vascular superoxide concentrations are limited by extracellular superoxide dismutase (EC-SOD), which is highly expressed in the vasculature of most animal species. Metalloporphyrins are low molecular weight, synthetic, redox-active, catalytic antioxidants that act as SOD mimetics. We evaluated the effects of metalloporphyrins on blood pressure in different animal species. The metalloporphyrin AEOL10113 (5-10 micro /kg iv), but not native or polyethylene glycol-CuZnSOD, caused a dose-dependent reduction in blood pressure in anesthetized rats. AEOL10113 had no effect on blood pressure in mice (wild-type or EC-SOD knockouts), guinea pigs, dogs, or baboons at doses up to 5 mg/kg iv Structure-activity studies indicated that metalloporphyrins with high SOD activity were more effective in lowering rat blood pressure than low-activity analogs. The blood pressure effect of AEOL10113 was not attributable to the release of manganese, nor was it affected by inhibitors of nitric oxide synthase (L-NAME) and guanylate cyclase (ODQ, 8-bromo-cGMP, and methylene blue) or nitric oxide scavengers (HbAo). Chlorpheniramine attenuated the effect, suggesting that the blood pressure response in rats is related to histamine release rather than the protection of nitric oxide.
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PMID:Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity. 1248 34

The mycobacterial Rv1625c gene product is an adenylyl cyclase with sequence similarity to the mammalian enzymes. The catalytic domain of the enzyme forms a homodimer and residues specifying adenosine triphosphate (ATP) specificity lie at the dimer interface. Mutation of these residues to those present in guanylyl cyclases failed to convert the enzyme to a guanylyl cyclase, but dramatically reduced its adenylyl cyclase activity and altered its oligomeric state. Computational modeling revealed subtle differences in the dimer interface that could explain the biochemical data, suggesting that the structural and catalytic features of this homodimeric adenylyl cyclase are in contrast to those of the heterodimeric mammalian enzymes.
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PMID:Mutational analysis of the Mycobacterium tuberculosis Rv1625c adenylyl cyclase: residues that confer nucleotide specificity contribute to dimerization. 1280 85

1. Physiological nitric oxide (NO) signal transduction occurs through activation of guanylyl cyclase (GC)-coupled receptors, resulting in cGMP accumulation. There are five possible receptors: four heterodimers (alpha1beta1, alpha2beta1, alpha1beta2, alpha2beta2) and a presumed homodimer (nubeta2). The present study investigated the kinetic and pharmacological properties of all these putative receptors expressed in COS-7 (or HeLa) cells. 2. All exhibited NO-activated GC activity, that of alpha1beta1 and alpha2beta1 being much higher than that of the beta2-containing heterodimers or nubeta2. All were highly sensitive NO detectors. Using clamped NO concentrations, EC(50) values were 1 nM for alpha1beta1 and 2 nM for alpha2beta1. With alpha1beta2, alpha2beta2 and nubeta2, the EC(50) was estimated to be lower, about 8 nM. 3. All the GCs displayed a marked desensitising profile of activity. Consistent with this property, the concentration-response curves were bell-shaped, particularly those of the beta2 heterodimers and nubeta2. 4. Confocal microscopy of cells transfected with the fluorescently tagged beta2 subunit suggested targeting to the endoplasmic reticulum through its isoprenylation sequence, but no associated particulate GC activity was detected. 5. The NO-stimulated GC activity of all heterodimers and nubeta2 was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and, except for nubeta2, was enhanced by the allosteric activator YC-1. 6. It is concluded that all the four possible heterodimers, as well as the putative nubeta2 homodimer, can function as high-affinity GC-coupled NO receptors when expressed in cells. They exhibit differences in NO potency, maximal GC activity, desensitisation kinetics and possibly subcellular location but, except for nubeta2, cannot be differentiated using existing pharmacological agents.
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PMID:Properties of NO-activated guanylyl cyclases expressed in cells. 1283 78

The role of nitric oxide (NO) in cardio-vascular homeostasis is now known to include allosteric redox modulation of cell respiration. An interesting animal for the study of this wide-ranging influence of NO is the cold-adapted Antarctic icefish Chionodraco hamatus, which is characterised by evolutionary loss of hemoglobin and multiple cardio-circulatory and subcellular compensations for efficient oxygen delivery. Using an isolated, perfused working heart preparation of C. hamatus, we show that both endogenous (L-arginine) and exogenous (SIN-1 in presence of SOD) NO-donors as well as the guanylate cyclase (GC) donor 8Br-cGMP elicit positive inotropism, while both nitric oxide synthase (NOS) and sGC inhibitors, i.e. L-NIO and ODQ, respectively, induce significant negative inotropic effects. These results therefore demonstrate that under basal working conditions the icefish heart is under the tonic influence of a NO-cGMP-mediated positive inotropism. We also show that the working heart, which has intracardiac NOS (shown by NADPH-diaphorase activity and immunolocalization), can produce and release NO, as measured by nitrite appearance in the cardiac effluent. These results indicate the presence of a functional NOS system in the icefish heart, possibly serving a paracrine/autocrine regulatory role.
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PMID:No hemoglobin but NO: the icefish (Chionodraco hamatus) heart as a paradigm. 1547 16

Collecting ducts are a major site of renal production and action of both prostaglandins and nitric oxide. Experiments were undertaken to examine whether nitric oxide regulates cyclooxygenase (COX)-2 expression and PGE(2) release in cultured collecting duct cells. In mIMCD-K2 cells, sodium nitroprusside (SNP) in the 50- to 800-microM range induced a marked dose- and time-dependent increase in COX-2 protein levels, determined by immunoblotting, and the induction was detectable at 4 h. This was preceded by induction of COX-2 mRNA as determined by real-time-RT-PCR. The COX-2 induction was accompanied by a significant rise in PGE(2) release as determined by enzyme immunoassay. S-nitroso-N-acetylpenicillamine (SNAP) had a similar stimulatory effect on COX-2 expression and PGE(2) release. 8-bromo-cGMP (200 microM) had no effect on COX-2 expression. The SNP-stimulated COX-2 expression was not affected by the guanylyl cyclase inhibitor methylene blue or the protein kinase G inhibitor KT-5823 (2.0 microM). In contrast, the SNP-stimulated COX-2 expression was significantly reduced by either the Erk1/2 inhibitor PD-98059 or the P38 inhibitor SB-203580 and was abolished by combination of the two kinase inhibitors. The stimulation was also significantly blocked by the SOD mimetic tempol. Thus we conclude that NO stimulates COX-2 expression in collecting duct cells through mechanisms involving MAP kinase and superoxide, but not cGMP.
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PMID:Nitric oxide stimulates COX-2 expression in cultured collecting duct cells through MAP kinases and superoxide but not cGMP. 1670 45

Soluble guanylate cyclase (sGC) uses a ferrous heme cofactor as a receptor for NO and once bound activates the enzyme for the conversion of GTP to cGMP. The heme cofactor in sGC does not bind oxygen, thereby allowing it to selectively bind NO despite a cellular concentration of oxygen (microM) that is much higher than signaling concentrations of nitric oxide (nM). The molecular details of this ligand discrimination against oxygen have emerged and allowed for predictions regarding ligand specificity in the sGC family. The results reported here show that Gyc-88E from Drosophila is a hemoprotein that binds oxygen, as well as NO and CO. All three ligands form 6-coordinate complexes. Gyc-88E is active as a homodimer (5600 +/- 243 nmol min(-1) mg(-1)) and is inhibited by O2, CO, and NO (3.2-, 2.9-, and 2-fold, respectively). The Km for GTP was 0.66 +/- 0.15 mM in air (273 microM oxygen) and 0.82 +/- 0.15 mM under anaerobic conditions. The Ki for oxygen was calculated to be 51 +/- 28 microM. The biochemical properties of Gyc-88E are unique for guanylate cyclases and suggest a possible function as an oxygen sensor.
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PMID:Ligand binding and inhibition of an oxygen-sensitive soluble guanylate cyclase, Gyc-88E, from Drosophila. 1804 74


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