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 addition of ANF to Percoll-purified liver plasma membranes produced a slight activation of guanylate cyclase; the ANF-stimulated cyclase activity was further increased upon the addition of ATP to the enzyme assay mixture. The effect of ATP to potentiate the cyclase activation was concentration-dependent, required Mg2+ as a divalent cation, and was seen with membranes from various tissues and cells. ATP increased the maximal velocity of the cyclase without a change in the affinity for GTP or ANF. Phosphorylation by ATP might not be involved since ANF-stimulated guanylate cyclase was enhanced by non-phosphorylating ATP analogues as well. Thus, an allosteric ATP binding site is suggested to participate in ANF-induced regulation of membrane-bound guanylate cyclase.
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PMID:Participation of adenosine 5'-triphosphate in the activation of membrane-bound guanylate cyclase by the atrial natriuretic factor. 288 66

Cell fractionation studies have been performed, in order to obtain insight into the subcellular distribution of Dictyostelium adenylate cyclase and guanylate cyclase and also to provide a starting point for further study and isolation of these enzymes and their regulatory components. Adenylate cyclase and cAMP receptors were found in the same membrane fractions, but were distributed different from the plasma membrane marker alkaline phosphatase. Guanylate cyclase was partially soluble, partially particulate. In isopycnic gradients, particulate guanylate cyclase was present in other fractions than cAMP receptors and adenylate cyclase, but in similar ones to alkaline phosphatase. These observations are consistent with the hypothesis that cell-surface cAMP receptors and adenylate cyclase interact via a membrane-bound G-protein, whereas the receptors activate guanylate cyclase via a cytosolic factor. The adenylate cyclase activity in membranes obtained by sucrose gradient centrifugation was retained in the presence of various detergents, while with the same detergents the activity of particulate guanylate cyclase was lost. This adenylate cyclase was solubilized as assessed by gel filtration and centrifugation experiments, and it behaved heterogeneous in fractionation studies. In gel filtration, the major component eluted at a position corresponding to a Stokes radius of 4-7 nm. A purification of about 70-fold as compared to the cell homogenate was obtained by affinity chromatography of adenylate cyclase on ATP-Sepharose. We conclude that cell fractionation provides useful starting material for isolation and further study of Dictyostelium adenylate cyclase.
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PMID:Cell fractionation, detergent sensitivity and solubilization of Dictyostelium adenylate cyclase and guanylate cyclase. 288 13

Three classes of vasodilators mediate their effects through the activation of guanylate cyclase and the increased synthesis of cyclic GMP. Nitrovasodilators such as nitroglycerin, nitroprusside, hydroxylamine, azide, etc. result in the generation of the nitric oxide free radical that activates the cytosolic (soluble) isoenzyme form of guanylate cyclase. These agents have been useful in increasing cyclic GMP synthesis in numerous model systems and these effects are independent of extracellular calcium. The increased synthesis of cyclic GMP and the activation of cyclic GMP-dependent protein kinase result in the altered phosphorylation of many smooth muscle proteins including the dephosphorylation of myosin light chain, which is associated with vascular and tracheal smooth muscle relaxation. These latter effects may result from cyclic GMP decreasing cytosolic free calcium concentrations and the activity of myosin light chain kinase. Another class of vasodilators, designated endothelium-dependent vasodilators, includes a long list of agents such acetylcholine, histamine, A23187, ATP, thrombin, etc. that relax vessels only when the endothelium is intact. These agents result in the increased endothelial synthesis and/or release of a factor(s) designated endothelial-derived relaxant factor (EDRF), the structure of which is unknown. This labile factor also activates the soluble isoenzyme form of guanylate cyclase in the smooth muscle resulting in cyclic GMP accumulation and the same cascade of events as above. There is evidence that even under basal, non-stimulated conditions there is EDRF release that influences vascular tone due to the increased synthesis of cyclic GMP. A third class of vasodilators, atrial natriuretic factor (ANF) or atriopeptins, includes a family of peptides that are produced in cardiac atria and other tissues and influence cardiovascular volume and dynamics by causing natriuresis, diuresis, vasodilation and decreased renin, aldosterone and vasopressin secretion. These peptide hormones also increase cyclic GMP synthesis in vascular, renal, adrenal and other tissues. These effects are mediated through specific ANF receptors that couple to and activate the membrane (particulate) isoenzyme form of guanylate cyclase and increase cyclic GMP-dependent protein kinase activity. There are two ANF receptor subtypes in most cells and tissues that are 130,000 and 66,000 daltons. The ANF receptor of about 130,000 daltons, designated receptor ANF-R1 copurifies with particulate guanylate cyclase through numerous procedures and may be part of the membrane-associated guanylate cyclase complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. 289 Jan 72

In the ciliated protozoan Paramecium, Ca2+ and cyclic nucleotides are believed to act as second messengers in the regulation of the ciliary beat. Ciliary adenylate cyclase was activated 20-30-fold (half-maximal at 0.8 microM) and inhibited by higher concentrations (10-20 microM) of free Ca2+ ion. Ca2+ activation was the result of an increase in Vmax., not a change in Km for ATP. The activation by Ca2+ was seen only with Mg2+ATP as substrate; with Mn2+ATP the basal adenylate cyclase activity was 10-20-fold above that with Mg2+ATP, and there was no further activation by Ca2+. The stimulation by Ca2+ of the enzyme in cilia and ciliary membranes was blocked by the calmodulin antagonists calmidazolium (half-inhibition at 5 microM), trifluoperazine (70 microM) and W-7 (50-100 microM). When ciliary membranes (which contained most of the ciliary adenylate cyclase) were prepared in the presence of Ca2+, their adenylate cyclase was insensitive to Ca2+ in the assay. However, the inclusion of EGTA in buffers used for fractionation of cilia resulted in full retention of Ca2+-sensitivity by the ciliary membrane adenylate cyclase. The membrane-active agent saponin specifically suppressed the Ca2+-dependent adenylate cyclase without inhibiting basal activity with Mg2+ATP or Mn2+ATP. The ciliary adenylate cyclase was shown to be distinct from the Ca2+-dependent guanylate cyclase; the two activities had different kinetic parameters and different responses to added calmodulin and calmodulin antagonists. Our results suggest that Ca2+ influx through the voltage-sensitive Ca2+ channels in the ciliary membrane may influence intraciliary cyclic AMP concentrations by regulating adenylate cyclase.
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PMID:Regulation of ciliary adenylate cyclase by Ca2+ in Paramecium. 289 52

Receptor-mediated regulation of guanylate cyclase is well-studied in intact Dictyostelium discoideum cells, but study of the enzyme in cell-free preparations has hampered. A major obstacle has been that in vitro guanylate cyclase activity could be detected only in the presence of unphysiological concentrations of Mn2+-ions. In this paper we report the identification of a guanylate cyclase in D.discoideum cell homogenates that has high activity with Mg2+-GTP. The enzyme is activated by non-hydrolyzable ATP and GTP analogues and inhibited by submicromolar concentrations of Ca2+-ions. We suggest that the presently identified enzyme is regulated in intact cells via cell surface receptors. The compounds that modulated the enzyme activity in vitro may reflect physiologically relevant regulation mechanisms.
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PMID:A magnesium-dependent guanylate cyclase in cell-free preparations of Dictyostelium discoideum. 289 90

1. Two directly-acting stimulants of soluble guanylate cyclase, glyceryl trinitrate (0.1 microM) and sodium azide (10 microM), and a receptor-mediated stimulant of particulate guanylate cyclase, atriopeptin II (10 nM), each elevated the cyclic GMP content of primary cultures of pig aortic endothelial cells without affecting the cyclic AMP content. 2. Two receptor-mediated stimulants of adenylate cyclase, glucagon (1 microM) and isoprenaline (10 microM), had no effect on the cyclic AMP or cyclic GMP content of these cells, but the directly acting stimulant, forskolin (30 microM), induced a small increase in cyclic AMP content. 3. Three agents that release endothelium-derived relaxing factor (EDRF); bradykinin (0.1 microM), ATP (10 microM) and ionophore A23187 (0.1 microM), each markedly elevated the cyclic GMP content of pig aortic endothelial cells, but acetylcholine (1 microM) had no effect. None of these agents had any effect on cyclic AMP content. 4. Two agents that potentiate the actions of EDRF; M & B 22948 (100 microM) and superoxide dismutase (30 units ml-1), each elevated the cyclic GMP content of pig aortic endothelial cells without affecting the cyclic AMP content. Pretreating cells with catalase (100 units ml-1) did not affect the rise in cyclic GMP content induced by superoxide dismutase (30 units ml-1). 5. Pretreatment of pig aortic endothelial cells with haemoglobin (10 microM) reduced the resting content of cyclic GMP and blocked the increase in cyclic GMP content induced by glyceryl trinitrate (0.1 microM), sodium azide (10 microM), bradykinin (0.1 microM), ATP (10 microM), ionophore A23187 (0.1 microM), M & B 22948 (100 microM) and superoxide dismutase (30 units ml-1), but not that induced by atriopeptin II (10 nM). 6. Pretreatment of pig aortic endothelial cells with an inhibitor of soluble guanylate cyclase, methylene blue (20 microM), had no effect on the resting content of cyclic GMP. Methylene blue (20 microM) blocked the increase in cyclic GMP content induced by glyceryl trinitrate (0.1 microM), M & B22948 (100 microM) and bradykinin (0.1 microM), but not that induced by atriopeptin II (10 nM). 7. The data show that soluble guanylate cyclase, particulate guanylate cyclase and adenylate cyclase are present in pig aortic endothelial cells. They further suggest that EDRF, produced spontaneously or in response to vasoactive agents, elevates endothelial cyclic GMP content by stimulating soluble guanylate cyclase. It is possible that this may serve as a feedback loop by which the endothelial cell modulates EDRF production.
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PMID:Endothelium-derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells. 289 77

The newly discovered peptide, brain natriuretic factor (BNF), caused a concentration-dependent increase (up to 400-fold) in intracellular cyclic GMP levels in cultured endothelial, smooth muscle and fibroblast cells. The extent of cGMP augmentation was comparable to that produced by atrial natriuretic factor (ANF). The activity of the membrane-bound guanylate cyclase of different rat tissues and cultured cells was markedly stimulated by the peptide and the addition of ATP potentiated the stimulation. As opposed to tissue particulate guanylate cyclase, the enzyme in cell membranes was slightly more sensitive to activation by BNF than to stimulation by ANF. On bovine aortic smooth muscle (BASM) cells, specific high-affinity binding sites (Bmax = 398 fmol/10(6) cells, Kd = 0.52 nM) for BNF were observed for which ANF could compete with apparently equal affinity. These results suggest that activation of the cGMP pathway constitutes a common mechanism of action for both BNF and ANF.
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PMID:Brain natriuretic factor. Augmentation of cellular cyclic GMP, activation of particulate guanylate cyclase and receptor binding. 289 3

LY 83583 (6-anilino-5,8-quinolinedione) has been reported to lower intracellular cyclic GMP by an unknown mechanism. The objective of the present study was to investigate the effect of LY 83583 on different types of vasorelaxation and to study its mechanism of action. Low concentrations of LY 83583 (less than or equal to 0.1 microM) inhibited endothelium-dependent relaxations of rabbit aortic strips induced by acetylcholine or by the calcium ionophore A23187. Higher concentrations (greater than or equal to 0.3 microM) were required to produce partial inhibition of relaxation to sodium nitroprusside and glyceryl trinitrate. Cyclic AMP-mediated relaxations, induced by isoprenaline or forskolin, were not affected by LY 83583 (10 microM). The site of interference of LY 83583 with endothelium-dependent relaxation was examined with endothelium-derived relaxing factor (EDRF) released from cultured endothelial cells that were grown on microcarrier beads and stimulated by superfusion with ATP or thimerosal. EDRF in the superfusate was detected by endothelium-denuded segments of rabbit femoral artery, which responded with dilation and, simultaneously, by purified soluble guanylate cyclase (GC) in test tubes, which was activated by EDRF. When LY 83583 was added to the glutathione-containing GC-assay or to the superfusate from cultured endothelial cells, it did not affect stimulation of soluble GC by EDRF but it slowly reversed the dilator response of the arterial detector segment. Superfusion of cultured endothelial cells with LY 83583 (1 microM), rapidly and reversibly inhibited EDRF release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:LY 83583 interferes with the release of endothelium-derived relaxing factor and inhibits soluble guanylate cyclase. 290 13

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilatations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such varying stimuli as increases in blood flow and hypoxia, as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells, resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented, which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.
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PMID:The role of endothelium in the control of vascular tone. 300 Mar 43

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such different stimuli as increases in blood flow and hypoxia as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23 187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.
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PMID:[Regulation of vascular tone by the endothelium]. 300 57


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