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)

The activity of calf uterus guanylate cyclase (EC 4.6.1.2) exists in at least two and most probably three distinct forms. The cytosolic enzyme exhibits hyperbolic substrate curves with respect to GTP and Mn2+, while the particulate cyclases (nuclear and microsomal)display sigmoidal (GTP) and hyperbolic (Mn2+) relationships. The Hill coefficient for the GTP dependence is 0.9 for the cytosolic, 1.5 for the nuclear, and 1.4 for the microsomal enzyme. The cytosolic enzyme has a Km for GTP of 70 muM while half maximal velocity occurs at 90 and 100 muM GTP for the nuclear and microsomal enzymes, respectively. The Ka for Mn2+ is 0.57, 0.71 or 0.75 mM for the cytosolic, nuclear, or microsomal enzyme, respectively.
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PMID:Guanylate cyclase. Existence of different forms and their regulation by nucleotides in calf uterus. 0 17

The effects of prostaglandins and bradykinin on the activity of guanylate cyclase in plasma membranes from rat uterus and duodenum have been found strongly dependent on calcium content.
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PMID:Effects of prostaglandins, calcium, and bradykinin on guanylate cyclase in different organs. 3 15

At extremely low concentrations, in the picomole and the nanomole range, bradykinin produces contraction and relaxation of smooth muscle in the gastrointestinal and the urogenital tract. At the target organ, bradykinin interacts with discriminator proteins of the plasma membranes and triggers, via changes in certain membrane functions, its biological response:--The binding to the discriminator makes specific conformative and constitutional demands on the nonapeptide. The binding results from an angular conformation which exists in the solution. The complete sequence is responsible for this specific conformation. Consequently, the biological activity of partial sequences is low. The conformational analysis of analogues used in studies on the mechanism of action showed but slight differences from bradykinin. The interaction of these analogues with the discriminator protein is disturbed to a varying extent by modifications at positions 1, 5, 8 and 9 in the side chains. The affinity for the discriminator is affected, dependently on the respective configuration, by substitution on the beta-C atom in the two phenylalanine residues.--Bradykinin is not only bound to, but also degraded at, the plasma membranes of the rat uterus and duodenum. The bradykinin-degrading enzyme has been characterized as a kininase II with the aid of various inhibitors. The conformative and configurative prerequisites decisive for enzymatic degradation are others than those decisive for binding to the discriminator.--The changes in the activities of the membrane-bound adenylate and guanylate cyclases (produced by the bradykinin-discriminator complex) that take place at the rat duodenum and uterus in the presence of extracellular calcium ions contrast with each other: At the duodenum, the ratio between these two cyclic nucleotides is changed in favour of adenylate cyclase; and at the uterus, in favour of guanylate cyclase; Substances which increase or decrease the cAMP level may also potentiate or inhibit the relaxation of the duodenum. These bradykinin-induced changes in enzyme activity must be considered in connection with other effectors, e.g. prostaglandins and calcium ions.--The calcium-ion-dependence of the effect of bradykinin on the guinea-pig ileum and the rat uterus indicates the importance of these ions as additional second messengers. Bradykinin stimulates the influx of calcium ions into the ileum; it is ineffective if no extracellular calcium ions into the ileum; it is ineffective if no extracellular calcium ions are available. It seems that intracellular and membranal calcium is mobilized in the uterus, which is evidenced by results from experiments with EGTA on the isolated organ and by the release of calcium from plasma membranes after application of bradykinin. It is assumed that the observed changes in membrane functions are induced by the peptide-discriminator complex simultaneously and not in the form of a causal chain.
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PMID:[On the mode of action of bradykinin on smooth muscle (author's transl)]. 39 90

1. Effects of atrial natriuretic peptide (ANP) on tension development, particulate guanylate cyclase activity and guanosine 3':5'-cyclic monophosphate (cyclic GMP) concentrations of uteri from oestrogen-treated, progesterone-treated, ovariectomized and pregnant rats were determined in vitro. 2. ANP inhibited the tension development by myometrial tissues from oestrogen-treated virgin rats and the sterile horn of 10 to 14 day pregnant rats but not of the uterus from pregnant and progesterone-treated rats. 3. Inhibition of cyclo-oxygenase and lipoxygenase activities did not restore the tocolytic activity of ANP on gravid uterus. ANP exerted a tocolytic effect on nongravid uterus submaximally stimulated by prostaglandin F2 alpha (PGF2 alpha), oxytocin, vasopressin, angiotensin II or 5-hydroxytryptamine (5-HT). 4. Ovariectomy decreased the tocolytic effects of ANP, which could be restored by oestrogen treatment. 5. The refractoriness to the tocolytic effect of ANP in pregnant rats was not accompanied by a decrease in its relaxant effects on isolated aortic strips. 6. Tocolytic effects of isoprenaline, isobutylmethyl xanthine and hydroxylamine were not influenced by pregnancy or progesterone treatment. Up to a concentration of 3 mM, sodium nitroprusside did not affect myometrial tension development. 7. Pregnancy and progesterone treatment markedly inhibited ANP-induced increases in myometrial particulate guanylate cyclase activity and cyclic GMP concentrations but did not influence the effects of ANP on aortic cyclic GMP concentrations. 8. It is concluded that exposure of the myometrium to circulating and placentally-produced progesterone is responsible for the pregnancy-induced decrease in the effects of ANP on myometrial particulate guanylate cyclase activity and cyclic GMP concentrations and in turn on myometrial tension development.
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PMID:Refractoriness of the gravid rat uterus to tocolytic and biochemical effects of atrial natriuretic peptide. 197 61

1) Eicosanoids are a family of polyunsaturated 20-carbon fatty acids and their metabolites. The metabolites are produced by three enzymatic pathways: the cyclooxygenase pathway, giving prostaglandins (PGs), the lipoxygenases and the epoxygenases pathways. Arachidonic acid (C20:4) is the most common fatty acid precursor in mammalian cells, where it is incorporated, as an ester, into the membrane lipid complex. 2) The eicosanoids have a variety of effects on several cell activities, including secretion, muscle contraction, cell growth and differentiation. The type of effect--stimulation or inhibition--depends on the metabolite, its concentration, the metabolic activity of the cell and the involvement of other humoral factors. 3) The message may be transmitted via a specific membrane receptor to a specific transduction system: the adenyl or guanyl cyclase system and mobilization of free cytosolic Ca2+, or via the participation of membrane ion channels. Depending on which is involved, the eicosanoid message applies to the cell in which it was synthesized or to neighboring cells (autocrine or paracrine action). 4) The eicosanoids, especially the PGs, take part in many reproductive processes; in the hypothalamic-pituitary axis, particularly through the synaptic modulation by PGE2 (stimulation of LHRH secretion and inhibition of noradrenaline secretion); in the ovary: follicle maturation and luteolysis; in the oviducts: gamete migration; in the uterus: ovum implantation and parturition. 5) PGs seem to have a variety of species-dependent effects on the normal onset of labor. In sheep there is an increase in fetal cortisol, a drop in the progesterone/estradiol ratio and increased PG synthesis. In women, there is an increase of phospholipase A2 activity in amnios and uterus with an increase of PGE2 in the first tissue and of PGF2 alpha in the second one. 6) The PGs from the seminal fluid have several actions. They effect fertility by acting on the female genital tract or on the spermatozoa. PGE1 and PGE2 influence the fertilization capacity. PGs also effect the process of ejaculation (inhibition of the stimulatory effect of noradrenaline). Finally, they effect the immune responses: PGEs and 19 hydroxy PGEs immuno-suppressive characteristics.
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PMID:[Prostaglandins and reproduction. I. Physiological aspects]. 201 23

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.
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PMID:Detection of a uteroglobin-like phospholipase A2 inhibitory protein in the circulation of rabbits. 274 26

Estrogens are known to increase cyclic guanosine monophosphate (cGMP) levels in the uterus of rats by enhancing guanylate cyclase (GC) activity. In the present study, the cytochemical localization of GC activity was studied in the uteri of immature and ovariectomized rats after treatment with diethylstilbestrol (DES), progesterone, estrogen antagonist (CI628), and a combination of DES and CI628. Twenty-four hours after the first dose of DES, moderate to strong guanylate cyclase activity was indicated by lead phosphate precipitate on the luminal microvillar and basolateral surfaces of epithelial cells, whereas strong activity was found on the plasma membranes of fibroblasts, endothelial cells, and myometrial cells. The enzyme activity in the epithelial cells declined slightly 24 hr after the second daily dose of DES. Uterine tissues from DES-treated rats that were preheated at 60 degrees C for 30 min or preincubated with a GC inhibitor showed no reaction product. Guanylate cyclase activity was not observed cytochemically in the uterine tissues of the vehicle control (immature or ovariectomized) or progesterone-and CI628-treated animals. Weak guanylate cyclase activity was observed on the plasma membranes of epithelial cells and endothelial cells after doses of DES and CI628 were given simultaneously. The biochemical assays of the total homogenate in vitro indicated that uterine GC showed about a twofold increase after one dose of DES and a 1.3-fold increase following two doses (one dose per day) of DES when compared with their respective nontreated controls, or with progesterone-treated uteri. GC was found in particulate (09%) and cytosol (10%) fractions. These data demonstrated that DES stimulated uterine guanylate cyclase activity, while progesterone and CI628 were ineffective at the doses used. Estrogen antagonist CI628 doses not completely suppress the effect of DES.
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PMID:Ultracytochemical localization of estrogen-stimulated guanylate cyclase in rat uterus. 612 Sep 72

We have shown previously that oestradiol elevates the cGMP content od isolated uterine horns incubated for 2 h with the hormone. Cycloheximide (30 micrograms/ml) or actinomycin D (100 micrograms/ml), at concentrations which markedly inhibit protein and RNA synthesis, blocked the oestrogen-induced increase in cGMP. These agents do not inhibit the rise in uterine cGMP content provoked by sodium nitroprusside, thus arguing against a direct toxic effect on the enzyme guanylate cyclase. alpha-Amanitin, even at very high concentrations (80 micrograms/ml), interfered much less efficiently with total RNA and protein synthesis and also failed to prevent the oestrogen-induced increase in cGMP content. Taken together, these observations indicate that oestrogen action on uterine cGMP concentration in vitro depends on an RNA and/or a protein biosynthetic event that takes places in the uterus. This therefore confirms and extends analogous observations made previously under conditions in vivo.
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PMID:Oestrogen-induced increase in uterine cGMP content in vitro: effects of inhibitors of protein and RNA synthesis. 617 45

Atrial natriuretic peptide (ANP) receptors were characterized in rat uterus. The binding of [125I]ANP to uterine membranes was completely competed for by increasing concentrations of unlabeled ANP (Kd = 0.39 nM) and brain natriuretic peptide (Kd = 1.24 nM) and partially by C-type natriuretic peptide (CNP; Kd = 80.4 nM), but not by C-ANF. Also, [125I]Tyr-CNP bound to uterine membranes was completely competed by unlabeled CNP (Kd = 1.12 nM). Cross-linking of [125I]ANP to uterine membranes revealed the presence of one band of 130 kilodaltons, corresponding to the guanylyl cyclase (GC-A and/or GC-B) subtypes of natriuretic peptide receptors. The presence of messenger RNA coding for genes of both GC-A and GC-B receptors was shown by quantitative reverse transcriptase polymerase chain reaction. Furthermore, ANP and, to a lesser degree, CNP stimulated the production of cGMP in rat uterus. Autoradiographic studies localized the highest binding of [125I]ANP in the endometrium, whereas [125I]Tyr-CNP binding was distributed in the endometrium as well as in the myometrium. These results demonstrate that rat uterine ANP receptors are of the guanylyl cyclase-coupled subtypes. The uterus is a target of natriuretic peptides where ANP induces its biological effects through the production of cGMP.
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PMID:Characterization and distribution of natriuretic peptide receptors in the rat uterus. 766 42

Cholinergic stimulation of vascular endothelin activates NO synthase (NOS), leading to generation of NO from arginine. This NO diffuses to the overlying vascular smooth muscle and causes vasodilatation. NOS has also been found in the central and peripheral nervous systems and it is clear now that NO plays an important role as a neurotransmitter. Here we investigate the role of NO in controlling contraction of uterine smooth muscle. Our previous work showed that NO activates the cyclooxygenase enzyme in the hypothalamus, leading to production of prostaglandin E2 (PGE2). We began by determining whether NO was involved in production of arachidonic acid metabolites in the uterus. Uteri were removed from female rats that had been treated with estrogen (17 beta-estradiol). Control animals were similarly injected with diluent. Tissues were incubated in vitro in the presence of [14C]arachidonic acid for 60 min. Synthesis of PGs and thromboxane B2 (TXB2) was markedly stimulated by sodium nitroprusside (NP), the releaser of NO. The effect was greatest on TXB2; there were no significant differences in increases of different PGs. The response to NP was completely prevented by Hb, a scavenger of NO. The inhibitor of NOS, NG-monomethyl-L-arginine (NMMA), significantly decreased synthesis of PGE2 but not the other prostanoids (6-keto-PGF1 alpha and PGF2 alpha). Addition of Hb to scavenge the spontaneously released NO inhibited synthesis of 6-keto-PGF1 alpha, PGE2, and PGF2 alpha, but not TXB2. There was a much lesser effect on products of lipoxygenase, such that only 5-hydroxy-5,8,11,14-eicosatetraenoic acid (5-HETE) synthesis was increased by NP, an effect that was blocked by Hb; there was no effect of NMMA or Hb on basal production of 5-HETE. Thus, NO stimulates release of the various prostanoids and 5-HETE; blockade of NOS blocked only PGE2 release, whereas Hb to scavenge the NO released also blocked synthesis of 6-keto-PFG1 alpha, PGE2, and PGF2 alpha, indicating that basal NO release is involved in synthesis of all these PGs, especially PGE2. Presumably, NMMA did not block NOS completely, whereas Hb completely removed released NO. This may explain the different responses of the various prostanoids to NMMA and Hb. To determine the role of these prostanoids and NO in control of spontaneous in vitro uterine contractility in the estrogen-treated uterus, the effect of blocking NOS with NMMA and of scavenging NO produced by Hb on the time course of spontaneous uterine contractility was studied. Surprisingly, blockade of NOS or removal of NO by Hb prevented the spontaneous decline in uterine motility that occurs over 40 min of incubation. We interpret this to mean that NO was released in the preparation and activated guanylate cyclase in the smooth muscle, resulting in production of cGMP, which reduces motility and induces relaxation. When the motility had declined to minimal levels, the effect of increased NO provided by NP was evaluated; apparently by stimulating the release of prostanoids, a rapid increase in motility that persisted for 10 min was produced. This effect was completely blocked by Hb. The action of NO was also blocked by indomethacin, indicating that it was acting via release of PGs. Apparently, when motility is low, activation of PG synthesis by NO to activate the cyclooxygenase enzyme causes a rapid induction of contraction, whereas, when motility is declining, NO acts primarily via guanylate cyclase to activate cGMP release; the action of the prostanoids released at this time is in some manner blocked.
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PMID:Role of nitric oxide in eicosanoid synthesis and uterine motility in estrogen-treated rat uteri. 790 54


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