Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the diminished vasodilatation characterizing tolerance to organic nitrates is associated with lower rises in 3', 5'-cyclic guanosine monophosphate (cGMP) levels, the possibility that nitrovasodilators desensitized guanylate cyclase (GC) when pre-incubated with coronary supernatants was studied. In the absence of cysteine, pre-incubation with nitroglycerin (NG) decreased GC-activity during subsequent incubation to 24 +/- 7% of control values, whereas six other nitrovasodilators had much smaller effects. When cysteine was present during pre-incubation, NG-stimulation of GC remained significantly higher (59 +/- 3%; P less than 0.05), whereas the effects of other nitrovasodilators were not significantly changed. We also found that GC-activity, when reduced by pre-incubation with NG could only be restored by readdition of native coronary supernatant, suggesting that the enzyme became inactivated. NG pre-incubation of GC (in contrast to coronary strips) almost completely abolished the direct and thiol-independent stimulatory effect of 3-morpholinosydnonimine (SIN-1) down to 4.5 +/- 0.2%, whereas pre-incubation with other nitrovasodilators reduced the stimulatory response to SIN-1 to only 59 to 98%. Increasing concentrations of NG during pre-incubation dose-dependently (IC50 = 0.13 mM) reduced the activating effect of SIN-1 during incubation. There was also a time dependence in NG-induced inactivation of GC which followed first order kinetics with a calculated half life of 2.5 min in the absence of a thiol. The latter was increased to 4.0 or 19.2 min, respectively, when glutathione or cysteine-methylester were present during pre-incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1989 Jan
PMID:Tolerance to nitroglycerin is caused by reduced guanylate cyclase activation. 256 81

A line of kidney cells (PK1) which does not possess measurable ANP binding but has an active particulate guanylate cyclase has been identified. The physical characteristics of this enzyme were compared with those of particulate guanylate cyclase and ANP receptors isolated from rat lung. Although receptor and enzyme appear to reside on the same protein in the lung while the cyclase from PK1 cells does not possess ANP binding activity, these proteins exhibit identical physical characteristics. Guanylate cyclase from PK1 cells and rat lung and ANP receptor from lung co-eluted during gel filtration chromatography, with a Stokes radius of 6.1 nm. Also, these activities co-migrated through sucrose density gradients with S20,w values of 10.4 to 10.9. Using these parameters, a molecular weight of about 270 kD was estimated for all three activities. Furthermore, these enzyme activities exhibited similar mobilities in isoelectric focusing gels, with a pI of 6.1. Thus, although particulate guanylate cyclase from lung presumably possesses receptor binding activity, it is physically identical to a form of this enzyme associated with no measurable binding activity. Possible explanations for these observations are discussed.
Mol Cell Biochem 1989 Oct 05
PMID:Comparison of particulate guanylate cyclase in cells with and without atrial natriuretic peptide receptor binding activity. 257 8

Previous biochemical and cytochemical studies have indicated that in human term placenta the enzyme guanylate cyclase (GC) is associated mostly with the cytosolic fraction of homogenates and localized on the syncytiotrophoblast microvillous border. In the present study we have shown cytochemically the GC particulate form in early human placenta using guanylyl-imidodiphosphate [Gpp(NH)p] as substrate and NaN3 as activator. In samples of placental villi taken from the 6th to 12th week of pregnancy, the GC reaction product was always found on the apposing Langhans cytotrophoblast and syncytiotrophoblast plasma membranes. Furthermore, GC was present on cells in mitosis of the Langhans cytotrophoblast. From the 11th week GC was also visible on basal plasma membranes of Langhans cytotrophoblast and on endothelial cells of fetal capillaries. In samples of human term placenta GC was detectable on the syncytiotrophoblast microvillous border. This suggests a shift of enzyme localization during pregnancy.
Cell Mol Biol 1989
PMID:Ultracytochemical localization of guanylate cyclase in early human placenta. 257 54

Uteroglobin (UG) or blastokinin is a steroid-dependent low molecular weight secretory protein in the rabbit. This protein has many immunomodulatory properties. Recently, UG has been reported to be a potent phospholipase A2 (E.C. 3.1.1.4) inhibitor and this property may explain, at least in part, the immunomodulatory/antiinflammatory effects of this protein. Although UG has been detected in many reproductive and non-reproductive tissues of the rabbit it has not been reported in the circulation of this animal. Here, we present biochemical and immunochemical evidence for the presence of a low molecular weight circulating protein with progesterone binding and phospholipase A2 inhibitory properties similar to rabbit uterine UG. The major organs which contribute UG-like protein in circulation seem to be the tracheobronchial tree and to a lesser extent the uterus. The concentration of this protein is much higher in the vicinity of these organs as compared to peripheral circulation. Phospholipase A2 (PLA2)-catalyzed reaction is the major pathway of arachidonic acid production from cell membrane phospholipids. Arachidonic acid participates in the stimulation of guanylate cyclase, adenylate cyclase, protein kinase C and release of calcium from intracellular stores. These processes are thought to be involved in cellular signal transduction. Arachidonic acid is also essential for eicosanoid synthesis and many eicosanoids (e.g. prostaglandins, leukotrienes, etc.) are proinflammatory. Thus, the UG-like protein by inhibiting PLA2 may play a vital role in the regulation of cellular signal transduction, control of inflammation and platelet aggregation.
Mol Cell Endocrinol 1989 Apr
PMID:Detection of a uteroglobin-like phospholipase A2 inhibitory protein in the circulation of rabbits. 274 26

The objective of this study was to investigate the effects of 4 beta-phorbol 12-myristate 13-acetate (4 beta-PMA)--a potent activator of protein kinase C--on the responsiveness of mouse Leydig cells to stimulation with rat atriopeptin II (rAP-II). We report that, in these cells, the stimulation of testosterone production by rAP-II could be inhibited in a dose-dependent manner by 4 beta-PMA (1-200 nM). In contrast, the basal steroidogenesis was stimulated 2-fold by 4 beta-PMA. There was no inhibition of testosterone production when the cells were stimulated with 8-bromo cyclic GMP (8Br-cGMP) in the presence of 4 beta-PMA. Furthermore, addition of 4 beta-PMA resulted in a marked reduction in the amount of cGMP accumulated in response to rAP-II stimulation. 4 alpha-Phorbol 12-myristate 13-acetate (4 alpha-PMA) was found to have no effect at all. The inhibitory effect of 4 beta-PMA on steroidogenesis could be completely reversed by the addition of 0.25 mM 3-isobutyl 1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Also, the 4 beta-PMA-induced lowering of cGMP content could be partially reversed by IBMX. Membrane fractions from cells treated with 4 beta-PMA or 4 alpha-PMA did not differ in their contents of either basal or rAP-II-stimulated guanylate cyclase activities. We conclude that the 4 beta-PMA-mediated inhibition of testosterone production by Leydig cells stimulated with rAP-II results from an activation of a phosphodiesterase enzyme, hypothetically through an activated protein kinase C. This leads to a reduction in the cellular cGMP content through an increased metabolic removal of cGMP formed in response to rAP-II stimulation.
Mol Cell Endocrinol 1988 Mar
PMID:Effect of a tumour-promoting phorbol ester on atrial peptide-induced testosterone production and cyclic GMP accumulation by isolated mouse Leydig cells. 283 43

Gonadotropin releasing hormone enhanced guanylate cyclase [E.C.4.6.1.2] two- to threefold in pituitary, testis, liver and kidney. Dose response relationships revealed that at a concentration of 1 nanomolar, gonadotropin releasing hormone caused a maximal augmentation of guanylate cyclase activity and that increasing its concentration to the millimolar range caused no further enhancement of this enzyme. There was an absolute cation requirement for gonadotropin releasing hormone's enhancement of guanylate cyclase activity as there was no increase without any cation present. Gonadotropin releasing hormone could increase guanylate cyclase activity with either calcium or manganese in the incubation medium but more augmentation was observed with manganese. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of gonadotropin releasing hormone.
Mol Cell Biochem 1985 Mar
PMID:Cation-dependent gonadotropin releasing hormone activation of guanylate cyclase. 285 14

Leukotriene C4 (LTC4) enhanced the association of mouse peritoneal macrophages (MPM) with Trypanosoma cruzi, increasing the proportion of MPM associating with parasites and the number of trypanosomes per MPM. LTC4 affected both cells since pretreatment of either one increased the association. LTC4 also enhanced MPM uptake of killed T. cruzi or latex beads, denoting stimulation of phagocytosis. However, since LTC4 pretreatment of rat heart myoblasts--nonphagocytic cells--also increased the association, host cell membrane alterations induced by LTC4 may also facilitate parasite invasion. Inhibition of MPM guanylate cyclase abrogated the LTC4 effect, suggesting a role for elevated levels of cyclic GMP. LTC4 also increased the rate of intracellular parasite killing by MPM. These results suggest that LTC4, occurring in inflammation such as develops in T. cruzi infection, regulates parasite clearance by MPM by increasing uptake and intracellular destruction.
Mol Biochem Parasitol 1985 Apr
PMID:Effects of leukotriene C4 on macrophage association with and intracellular fate of Trypanosoma cruzi. 285 21

We have examined the properties of soluble guanylate cyclase activity in the human neutrophil. The enzyme showed complex regulation by metal ions. A 10-fold higher activity was observed in the presence of Mn2+ than Mg2+, while Ca2+ caused an increase in activity only in the presence of Mg2+ ion. Sodium nitroprusside (SNP), azide and hydrogen peroxide were activators of the enzyme. Dithiothreitol blocked the activation by SNP, suggesting the involvement of thiol groups in the activation process. Carbachol acting through the muscarinic cholinergic receptor caused a dose-dependent activation, which was blocked by atropine. Higher concns of carbachol were required to activate guanylate cyclase than were required for the modulation of enzyme release elicited by N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Nordihydroguaracetic acid inhibited carbachol stimulation of guanylate cyclase. By contrast, trifluoperazine (TFP), a calmodulin antagonist, caused a biphasic modulation of basal activity in the presence or absence of carbachol. Our results indicate that: allosteric interactions of metal ions are important to the regulation of the enzyme, the free radical nitroxide as well as hydrogen peroxide enhances enzyme activity, agonist occupancy of the muscarinic cholinergic receptor activates neutrophil guanylate cyclase probably through a mechanism involving calcium influx and the activation of the lipoxygenase pathway, and a TFP-sensitive site (possibly calmodulin) is involved in the selective regulation of basal enzyme activity.
Mol Immunol 1985 Jul
PMID:Regulation of human neutrophil guanylate cyclase by metal ions, free radicals and the muscarinic cholinergic receptor. 286 50

According to our present understanding organic nitrates like glycerine trinitrate mediate their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E.C. 4.6.1.2.) [1, 10]. The exact molecular mechanism underlying the process of enzyme activation is still a matter of controversial discussion. But there is general agreement in literature about the fact that organic nitrate compounds are able to activate the enzyme guanylate cyclase only in the presence or by the interaction of the amino acid cysteine [3, 5]. The stimulatory activity of nitric oxide-containing compounds may be due, at least in part, to the formation of active, unstable intermediate S-nitrosothiols, i.e. S-nitrosocysteine in case of the organic nitrates [7]. According to Craven and DeRubertis [2], the active intermediates of guanylate cyclase stimulation are represented by nitric oxide-heme complexes. There is, however, substantial evidence that the organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis, nitric oxide radicals are reductively split off the molecule from which (via the intermediate formation of salpetric acid) the nitric oxide is liberated as the essential stimulatory agent. In this study we examined the transformation of glycerine trinitrate and other organic nitrates under the influence of different thiols and a purified soluble rat liver guanylate cyclase preparation. At the same time the stimulation of guanylate cyclase in the presence of the thiols mentioned was quantitatively estimated. Only in case of cysteine did we find a strict correlation between the liberation of nitric oxide from different organic nitrates and the degree of enzyme activation. Several other thiols were also able to liberate nitric oxide, but surprisingly enough, there was no equivalent stimulation of guanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1985 Sep
PMID:Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase. 286 57

Adenylate and guanylate cyclase activities were demonstrated in R3230AC rat mammary adenocarcinomas by electron microscopic cytochemistry. Adenylate (AC) and guanylate (GC) cyclases were detected on plasma membrane of tumor epithelial cells, but not on fibroblasts and endothelial cells in the perivascular space. Both AC and GC activities were enriched in tumor epithelial cells at the periphery of the tumor lobular parenchyma rather than in cells in central core of the lobular parenchyma. Furthermore, the tumor cell plasma membranes facing the connective tissue stroma were in paucity or devoid of either enzyme activity. These heterogeneous distributions of both AC and GC among tumor epithelia suggest that R3230AC epithelial cells in different parts of the tumor mass may vary significantly in their regulation of cellular physiology.
Virchows Arch B Cell Pathol Incl Mol Pathol 1985
PMID:Heterogeneous localization of adenylate and guanylate cyclases in R3230AC rat mammary adenocarcinoma cells. 286 31


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