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)

Three isoforms of cyclic nucleotide phosphodiesterase (PDE) have been recently isolated from aortic tissue and two of them specifically hydrolyzed adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3':5'-cyclic monophosphate (cGMP), respectively (Lugnier et al., Biochem. Pharmac. 35, 1743, 1986). The role of these forms in controlling cyclic nucleotide levels and smooth muscle tone was investigated by the use of PDE inhibitors. The effects of selective inhibitors of the two forms specifically hydrolyzing cAMP or cGMP (cAMP-PDE and cGMP-PDE, respectively) were compared to those of non-selective inhibitors of the three aortic PDE forms, including the calmodulin-sensitive one (CaM-PDE). Relaxation responses and accumulation of tissue cAMP and cGMP induced by these drugs were studied in precontracted rat isolated aorta, and compared to the effects of isoprenaline and forskolin (stimulants of adenylate cyclase) or sodium nitroprusside (SNP) and sodium azide (stimulants of guanylate cyclase). The eight PDE inhibitors tested all relaxed aorta with potencies that correlated with their potencies as inhibitors of cAMP-PDE, but not of cGMP-PDE. At a concentration producing half-maximal relaxation, all PDE inhibitors induced a moderate but significant accumulation of cAMP, which was comparable to the accumulation of cAMP elicited by half-maximally relaxing concentrations of adenylate cyclase stimulating agents. At this concentration, some PDE inhibitors (M&B 22,948, dipyridamole and to a lesser extent, trequinsin) also induced a significant increase in cGMP levels, of the same order of magnitude as that caused by agents stimulating guanylate cyclase. However, the cGMP-increasing effect of these inhibitors was dissociated from their relaxing effect. In particular, the relaxing concentrations of M&B 22,948 (a selective inhibitor of cGMP-PDE) were clearly higher than the cGMP-increasing concentrations of the compound. At a concentration at which they elicited 10% relaxation by themselves, the selective cAMP-PDE inhibitor, rolipram, as well as the mixed inhibitor of cAMP- and cGMP-PDE, AAL 05 (a cilostamide analogue) enhanced both the cAMP-increasing and the relaxing effect of isoprenaline. Under the same conditions, no clear enhancement of the relaxation induced by SNP was observed. Only M&B 22,948 showed a slight potentiating effect on SNP-induced relaxation, but this effect was limited to low concentrations of SNP (less than 10 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of cyclic AMP- and cyclic GMP-phosphodiesterases in the control of cyclic nucleotide levels and smooth muscle tone in rat isolated aorta. A study with selective inhibitors. 282 8

Ultracytochemical localizations of cyclic nucleotide-metabolizing enzymes, namely adenylate cyclase (AC), guanylate cyclase (GC) and cyclic 3',5'-nucleotide phosphodiesterase (PDE), have been demonstrated in the human term placenta. AC activity was found positive on the basal plasma membrane of the syncytiotrophoblast and on the pinocytotic vesicle of the fetal capillary endothelial cell. GC activity was observed to be strong on the plasma membrane of the microvilli of the syncytiotrophoblast. The cAMP PDE activity was shown positive both on the basal plasma membrane and on the microvillous membrane, while cGMP PDE activity was exclusively confined to the microvilli of the syncytiotrophoblast. These observations suggest that the syncytiotrophoblast plays an important role in the cyclic nucleotide metabolism in the human term placenta and that there might be significant functional differences between its basal plasma membrane and its microvillous membrane.
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PMID:Ultracytochemical localizations of adenylate cyclase, guanylate cyclase and cyclic 3',5'-nucleotide phosphodiesterase activity on the trophoblast in the human placenta. Direct histochemical evidence. 289 56

It has been shown recently that astroglial cells of the mammalian CNS possess receptors for neurotransmitters. In order to analyze what sequences of cellular events occur upon activation of these glial receptors, we utilized a 5-HT receptor in a rat clonal cell of glial origin as a model system. When the C6BU-1 glioma cells were exposed to 5-HT, the cytosolic Ca2+ concentration ([Ca2+]i) was elevated and the cellular content of cGMP was increased in a dose-dependent manner. 5-HT receptor antagonists and a Ca2+ entry blocker suppressed the increases in both [Ca2+]i and cGMP. The magnitude of the cGMP increment depended on the environmental Ca2+ concentration and was totally blocked by Ca2+ depletion. Application of a Ca2+ ionophore increased [Ca2+]i and cGMP. There was a tendency for extremely high [Ca2+]i to suppress the cGMP increment. On the contrary, membrane-permeable cyclic nucleotide analogs failed to increase [Ca2+]i. These results suggest that the following sequence of events occurs in 5-HT-induced C6BU-1 cells: activation of 5-HT receptors, Ca2+ influx, a rise in [Ca2+]i, activation of guanylate cyclase, and, finally, activation of cyclic nucleotide phosphodiesterase.
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PMID:Cytosolic calcium elevation and cGMP production induced by serotonin in a clonal cell of glial origin. 301 93

In the aortas and mesenteric arteries from spontaneous hypertensive rats and in the aortas from stress- and desoxycorticosterone-acetate-hypertensive rats, the intracellular cGMP: cAMP ratios were significantly elevated when compared to the ratios in the aortas of the respective controls. Decreases in the intracellular cAMP or cGMP levels were consistently associated with increased activity of the cyclic-nucleotide-specific low K(m) phosphodiesterase (3':5'-cAMP 5' nucleotidohydrolase, EC 3.1.4.17). Increases in intracellular cGMP levels were associated with elevated guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity. Furthermore, adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity was less sensitive to stimulation by the beta-adrenergic stimulant isoproterenol in both the aortas and the hearts of the hypertensive animals. These changes could provide the biochemical basis for the (a) increased vascular smooth muscle tone and peripheral resistance observed in these animals, (b) increased reactivity to norepinephrine, and (c) decreased ability of aortas from hypertensive rats to relax. The presence of these same effects in different etiologic types of hypertension indicates that this aberration in cyclic nucleotide metabolism may represent a common metabolic defect basic to the hypertensive syndrome irrespective of etiology.
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PMID:Aberrations of cyclic nucleotide metabolism in the hearts and vessels of hypertensive rats. 415 74

At the end of metamorphosis, the intersegmental muscles of the moth Antheraea polyphemus undergo rapid degeneration in response to the peptide eclosion hormone (EH). Muscle death was preceded by a 22-fold increase in muscle guanosine-3',5'-cyclic monophosphate (cGMP) titers, which peaked 60 min after peptide exposure; adenosine-3'5'-cyclic monophosphate (cAMP) titers remained unchanged. EH induced a dose-dependent increase in muscle cGMP content with a threshold dose similar to that needed to induce cell death. Exogenous cGMP, but not cAMP, mimicked the action of EH. Sodium nitroprusside, a potent stimulator of guanylate cyclase, and methylated xanthines, a class of 3',5'-cyclic-nucleotide phosphodiesterase inhibitors, also induced the selective death of these muscles. It is concluded that an elevation of cGMP level is involved in EH-induced muscle degeneration. The intersegmental muscles become sensitive to EH at the end of adult development in response to the declining titers of the steroid molting hormones, the ecdysteroids. At earlier times, treatment with EH, exogenous cGMP, sodium nitroprusside, or methylated xanthines was ineffective in causing cell death. Nevertheless, treatment with EH at this time resulted in a marked increase in intersegmental-muscle cGMP. Thus, the onset of physiological responsiveness to the peptide hormone presumably results from biochemical changes distal to the EH receptors and guanylate cyclase.
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PMID:Cyclic GMP may serve as a second messenger in peptide-induced muscle degeneration in an insect. 609 17

Cyclic nucleotide phosphodiesterase [EC 3.1.4.17] was examined in tetrahymena pyriformis strain NT-1. Enzymic activity was associated with the soluble and the particulate fractions, whereas most of the cyclic GMP phosphodiesterase activity was localized in the soluble fraction; the activities were optimal at pH 8.0-9.0. Although very low activities were detected in the absence of divalent cations, they were significantly increased by the addition of either Mg2+ or Mn2+. A kinetic analysis of the properties of the enzymes yielded 2 apparent K(m) values ranging in concentration from 0.5 to 50 micron and from 0.1 to 62 micron for cyclic AMP and GMP, respectively. A Ca2+ -dependent activating factor for cyclic nucleotide phosphodiesterase was extracted from Tetrahymena cells, but this factor did not stimulate guanylate cyclase [EC 4.6.1.2] activity in this organism. On the other hand, tetrahymena also contained a protein activator which stimulated guanylate cyclase in the presence of Ca2+, although this activator did not stimulate the phosphodiesterase. The results suggested that Tetrahymena might contain 2 types of Ca2+ -dependent activators, one specific for phosphodiesterase and the other for guanylate cyclase.
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PMID:Studies on cyclic nucleotide metabolism in Tetrahymena pyriformis: partial characterization of cyclic AMP- and cyclic GMP-dependent phosphodiesterases. 610 21

We previously isolated a Ca2+-binding protein from a ciliate, Tetrahymena, and designated it as TCBP (Tetrahymena Ca2+-binding protein). The present paper reports that TCBP, which has two high affinity Ca2+-binding sites (Kd=4.6 X 10(-6) M), could activate porcine brain cyclic nucleotide phosphodiesterase at a concentration of over 10(-6) M free Ca2+, with the same mode of activation as that of authentic (porcine brain) calmodulin. In addition, the amino acid composition of TCBP was essentially the same as that of brain calmodulin. Therefore, we conclude that TCBP as an activator of Tetrahymena guanylate cyclase is indeed a calmodulin.
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PMID:Tetrahymena calcium-binding protein is indeed a calmodulin. 611 60

Theophylline, a cyclic nucleotide phosphodiesterase inhibitor, increases the rate of tyrosine aminotransferase (TAT) degradation in rat hepatoma tissue culture (HTC) cells. Theophylline (0.1-10 mM) causes a two- to five-fold increase in intracellular cAMP concentration but a 30-60% decrease in cGMP concentration. The decrease in cGMP occurs at doses of theophylline which increase the rate of TAT degradation. When cGMP levels are increased by incubating the cells with either Mn2+, an activator of guanylate cyclase, or 8-bromo-cGMP, an analog of cGMP, the effect of theophylline is reversed and the rate of TAT degradation is slowed. Thus, the rate of TAT degradation is inversely related to the concentration of cGMP in HTC cells. This raises the possibility that a cGMP-dependent event is involved in the control of specific protein degradation.
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PMID:The involvement of cyclic GMP in tyrosine aminotransferase degradation in rat hepatoma tissue culture cells. 611 61

Effect of a novel compound, 14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamenine (vinpocetine, TCV-3B), on the cyclic nucleotide metabolism and in vitro response of a vascular strip was investigated. The concentration of vinpocetine producing relaxation of the canine basilar arterial strip induced by 30 microM arachidonate peroxide was 3 microM. Cyclic GMP content in the vascular strip increased dose-dependently by addition of vinpocetine, and 2.5-fold elevation of cyclic GMP content in the vascular strip was observed by 10 microM vinpocetine. Administration of vinpocetine concentrations ranging from 1 to 100 microM did not produce a significant increase in cyclic AMP of the vascular strip. Vinpocetine did not stimulate guanylate cyclase, but selectively inhibited Ca2+-calmodulin dependent phosphodiesterase (Ca2+-PDE). Increase in cyclic GMP by vinpocetine is due to inhibition of Ca2+-PDE because Ca2+-PDE is known to hydrolyze cyclic GMP preferentially. Our results suggest that vinpocetine, a selective Ca2+-PDE inhibitor, produces relaxation of the vascular strip by the increase in cyclic GMP.
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PMID:[Effect of vinpocetine (TCV-3B), a vasodilator agent, on cyclic nucleotide metabolism]. 613 34

The cellular distribution of guanylate cyclase (EC 4.6.1.2), guanosine 3',5'-phosphate (cyclic GMP), cyclic GMP-dependent protein kinase (EC 2.7.1.38), and cyclic GMP phosphodiesterase (EC 3.1.4.17) have been examined in the rostral rat caudate-putamen complex. Immunofluorescent staining for guanylate cyclase, cyclic GMP, and cyclic GMP-dependent protein kinase in fresh frozen caudate-putamen tissues is analogous to the immunoperoxidase localization in perfusion-fixed striatal slices. Homologous immunoreactivity in the cytoplasm and processes of ovoid and rounded neurons, 15-20 microns in diameter can be seen for these three components of the cyclic GMP system. Immunoreactive neurons are uniformly distributed throughout the caudate-putamen complex of all experimental tissue examined. Occasional large neurons, greater than 25 microns in diameter, in the ventral region of the striatum show immunoreactivity. Enzyme histochemical determination of the activities of guanylate cyclase and cyclic GMP phosphodiesterase show the medium-sized neuronal population (15-20 microns) contain hydrolytic activity for these proteins. Large- to medium-sized capillaries demonstrate guanylate cyclase synthetic activity, but the endothelial cells do not exhibit immunohistochemical staining. This suggests that physiological activity of an enzyme cannot be completely discerned through application of immunohistochemical procedures. Additionally, enzymatically detected guanylate cyclase histochemical activity was not uniformly distributed throughout the striatal neuropil. Enzyme histochemical detection of cyclic GMP phosphodiesterase demonstrates homologous cellular staining to guanylate cyclase enzymatic reactivity. The activity of the phosphodiesterase hydrolytic enzyme could be detected evenly distributed throughout the neuropil within cells 15-20 microns in diameter, analogous in cytoarchitecture to immunohistochemically visualized guanylate cyclase, cyclic GMP, and protein kinase elements. Ultrastructural examination of rat caudate-putamen demonstrates that the immunoreactivity for the components of the cyclic GMP system is predominantly distributed within the medium-spiny neuron subtype of this structure. Occasional aspiny neurons demonstrate peroxidase immunoreactivity for the cyclase, cyclic GMP, and the protein kinase, as does the luminal surface of capillary endothelial cells. The subcellular distribution of the antigenic determinants for these three elements and the hydrolytic activity of the phosphodiesterase enzyme show proximity to one another and are confined to the postsynaptic region of asymmetrical, but not symmetrical, terminal boutons. The asymmetrical terminal population of the caudate-putamen is derived from striatal afferents from the neocortex, intralaminar thalamus, and substantia nigra, and to a lesser extent the intrinsic striatal circuitry.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Distribution of components of the guanosine 3',5'-phosphate system in rat caudate-putamen. 613 69


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