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)

STa, the heat-stable enterotoxin of Escherichia coli, is a specific activator of membrane-bound guanylyl cyclase and stimulates secretion of Cl- in a human colonic carcinoma cell line (T84). We investigated the effect of the cholinergic agent carbachol on the secretory response to STa. T84 cell monolayers were studied under voltage-clamped conditions in modified Ussing chambers. Simultaneous addition of STa and carbachol resulted in a biphasic synergistic response characterized by a brief peak in short-circuit current (Isc) followed by a prolonged plateau phase lasting up to 90 min. A synergistic response was also seen with sequential addition of the agonists, and was altered by the order and timing of agonist addition. Pretreatment with STa enhanced the synergistic response to carbachol, while the reverse order of additions produced synergy only when STa was added during or immediately after the Isc response to carbachol. Synergy occurred only with a concentration of STa sufficient to produce an Isc response alone. However, a concentration of carbachol that caused neither an increase in Isc nor intracellular Ca2+ mobilization was sufficient to evoke a synergistic response. Addition of 8-bromoguanosine 3',5'-cyclic monophosphate also produced a synergistic Isc response with carbachol, although maximal synergism was seen with simultaneous addition. Augmentation of the intracellular Ca2+ response to carbachol by STa is not the mechanism of synergy. Although the mechanism of synergy is not understood, these studies suggest that STa-induced cGMP interacts with other second messengers to produce the synergistic response, and that multiple intracellular mediators may influence the ability of STa to cause disease.
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PMID:Characterization of the synergistic interaction of Escherichia coli heat-stable toxin and carbachol. 165 72

Endothelial relaxing factor has been identified as nitric oxide, formed from L-arginine by the soluble enzyme nitric oxide synthase. Nitric oxide inhibits platelet aggregation and adhesion by stimulating a soluble guanylate cyclase and increasing the intracellular concentration of cyclic GMP. Nitrovasodilators, such as sodium nitroprusside, release the active moiety, nitric oxide. In the present study, we have investigated the effect of sodium nitroprusside and of a permeable cGMP derivative on the aggregation and ATP secretion of human platelets stimulated with the protein kinase C activators 1-oleoyl-2-acetylglycerol or 4 beta-phorbol-12- myristate-13-acetate. Human platelets were treated with lysine acetylsalicylate, washed and resuspended in Tyrode-buffered solution. ATP secretion was evaluated by luciferin-luciferase luminescence. Nitroprusside (4-40 microM) or 8-Br-cGMP (0.1-2.4 mM) inhibited both platelet aggregation and ATP secretion evoked by 1-oleoyl-2-acetylglycerol (40 microM) or 4 beta-phorbol-12-myristate-13- acetate (4 nM) in a dose-dependent manner, in the presence of the selective inhibitor of cGMP phosphodiesterase, M&B 22948 (5 microM). The inhibitory effect of nitroprusside was reversed by hemoglobin, known to bind and inactivate nitric oxide. To study the calcium-dependent pathway, we treated platelets with the ionophore ionomycin. The ensuing aggregation and ATP secretion were rapid and were dependent on agonist concentration. Nitroprusside (4-40 microM) inhibited the aggregation evoked by ionomycin (0.4 microM) as well as ATP release, in a dose-dependent manner. We conclude that cGMP is able to inhibit both the protein kinase C-dependent and the calcium-dependent pathways leading to platelet activation.
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PMID:Nitrovasodilators and cGMP inhibit human platelet activation. 166 Mar 21

Previous work has shown that streamer F (stmF) mutants of Dictyostelium discoideum exhibit prolonged chemotactic elongation in aggregation fields. The mutants carry an altered structural gene for cyclic GMP phosphodiesterase resulting in low activities of this enzyme. Chemotactic stimulation by cyclic AMP causes a rapid transient increase in the cyclic GMP concentration followed by association of myosin heavy chains with the cytoskeleton. Both events persist several times longer in stmF mutants than in the parental strain, indicating that the change in association of myosin with the cytoskeleton is transmitted directly or indirectly by cyclic GMP. We measured the cyclic AMP-induced Ca2+ uptake with a Ca(2+)-sensitive electrode and found that Ca2+ uptake was prolonged in stmF mutants but not in the parental strain. The G alpha 2 mutant strain HC33 (fgdA), devoid of InsP3 release and receptor/guanylate cyclase coupling, lacked Ca2+ uptake. However, the latter response and cyclic GMP formation were normal in the signal-relay mutant strain agip 53 where cyclic AMP-stimulated cyclic AMP synthesis is absent. LiCl, which inhibits InsP3 formation in Dictyostelium, blocked Ca2+ uptake in a dose-dependent manner. The data indicate that the receptor-mediated Ca2+ uptake depends on the InsP3 pathway and is regulated by cyclic GMP. The rate of Ca2+ uptake was correlated in time with the association of myosin with the cytoskeleton, suggesting that Ca2+ uptake is involved in the motility response of the cells.
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PMID:Mutant analysis suggests that cyclic GMP mediates the cyclic AMP-induced Ca2+ uptake in Dictyostelium. 166 42

The effect of endothelin (ET) on cyclic GMP levels in cultured porcine kidney epithelial cells, LLC-PK1, was investigated. ET-1 or ET-3, but not big ET-1 or ET C-terminal hexapeptide 16-21, elevated cyclic GMP levels in a concentration-dependent manner with an EC50 value of about 5 x 10(-10) M. This effect of ET-1 was enhanced with superoxide dismutase, diminished with oxyhemoglobin, inhibited with methylene blue, totally dependent on extracellular calcium and unaffected by indomethacin. L-Arginine derivatives, NG-methyl-L-arginine and NG-nitro-L-arginine also inhibited cyclic GMP responses to 10(-8) M ET-1 with IC50 values of 1.2 x 10(-6) M and 7.6 x 10(-8) M, respectively, and the inhibition was prevented with L-arginine. These data strongly suggest that ET-1 stimulates formation of an endothelium-derived relaxing factor-like substance from L-arginine or a related endogenous material(s) in a Ca(++)-dependent fashion, which in turn activates soluble guanylate cyclase to elevate cellular cyclic GMP levels. The concentrations required for these effects were 10 times lower than those required for atrial natriuretic factor. Thus, the effects of ET on cyclic GMP accumulation may be related to the natriuretic effects of ET in vivo.
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PMID:Endothelin increases cyclic GMP levels in LLC-PK1 porcine kidney epithelial cells via formation of an endothelium-derived relaxing factor-like substance. 166 72

Guanylyl cyclase from bovine rod outer segments was solubilized using Triton X-100 and a high concentration of KCl, and its regulation was studied. The efficiency of solubilization was about 50-90% of total activity. When the Ca2+ content was lowered (less than 80 nM), guanylyl cyclase was activated about 2-fold. In the presence of higher concentrations of Ca2+ (greater than 140 nM), the activity was decreased. The regulation by Ca2+ was also demonstrated with solubilized preparations. In the presence of 186 nM Ca2+ which inhibited guanylyl cyclase, La3+ activated the enzyme about 2-fold, suggesting that the Ca2(+)-binding protein similar to other Ca2(+)-binding proteins associates with guanylyl cyclase regulation. Sodium nitroprusside and nitric oxide which are activators of soluble guanylyl cyclase in other tissues also activated the retinal guanylyl cyclase. Maximum activation by sodium nitroprusside was 20-fold using Mg2+ as a cofactor. Activation by nitric oxide and related compounds suggests that retinal guanylyl cyclase contains a heme prosthetic group that may participate in a novel regulatory mechanism for this enzyme.
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PMID:Solubilization of guanylyl cyclase from bovine rod outer segments and effects of lowering Ca2+ and nitro compounds. 167 74

This study evaluates the role of N-hydroxylamine (NH2OH) in activating soluble guanylate cyclase in the mouse neuroblastoma clone N1E-115. It has been proposed that NH2OH is a putative intermediate in the biochemical pathway for the generation of nitric oxide (NO)/endothelium-derived relaxing factor (EDRF) from L-arginine. NH2OH caused a time- and concentration-dependent increase in cyclic GMP formation in intact cells. This response was not dependent on Ca2+. In cytosol preparations the activation of guanylate cyclase by L-arginine was dose-dependent and required Ca2+ and NADPH. In contrast, NH2OH itself did not activate cytosolic guanylate cyclase but it inhibited the basal activity of this enzyme in a concentration-dependent manner. The formation of cyclic GMP in the cytosolic fractions in response to NH2OH required the addition of catalase and H2O2. On the other hand, catalase and/or H2O2 lead to a decrease in L-arginine-induced cyclic GMP formation. Furthermore, NH2OH inhibited L-arginine- and sodium nitroprusside-induced cyclic GMP formation in the cytosol. The inhibition of L-arginine-induced cyclic GMP formation in the cytosol by NH2OH was not reversed by the addition of superoxide dismutase. These data strongly suggest that NH2OH is not a putative intermediate in the metabolism of L-arginine to an activator of guanylate cyclase.
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PMID:N-hydroxylamine is not an intermediate in the conversion of L-arginine to an activator of soluble guanylate cyclase in neuroblastoma N1E-115 cells. 167 45

Vertebrate retinal photoreceptors recover from photoexcitation-induced hydrolysis of guanosine 3', 5'-monophosphate (cyclic GMP) by resynthesizing cyclic GMP, which reopens cation channels that have been closed by light. Activation of guanylate cyclase by light-induced depletion of cytosolic calcium is a key event in this recovery process. This cyclase has now been shown to be regulated by a 23-kilodalton calcium binding protein. The protein is present in both rod and cone photoreceptors and was named recoverin because it promotes recovery of the dark state. The amino acid sequence of recoverin exhibits three potential calcium binding sites (EF hands). That recoverin binds calcium was confirmed with calcium-45 and by observing calcium-induced changes in its tryptophan fluorescence. Recoverin activated guanylate cyclase when free calcium was lowered from 450 to 40 nM, an effect that was blocked by an antibody to recoverin. Thus, guanylate cyclase in retinal rods is stimulated during recovery by the calcium-free form of recoverin. A comparison of recoverin with other calcium binding proteins reveals that it may represent, along with the protein visinin, a family of proteins that are regulated by submicromolar calcium concentrations.
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PMID:Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. 809 96

The resynthesis of cGMP in vertebrate photoreceptors by guanylate cyclase is one of the key events leading to the reopening of cGMP-gated channels after photoexcitation. Guanylate cyclase activity in vertebrate rod outer segments is dependent on the free calcium concentration. The basal activity of the enzyme observed at high concentrations of free calcium (greater than 0.5 microM) increases when the free calcium concentration is lowered into the nanomolar range (less than 0.1 microM). This effect of calcium is known to be mediated by a soluble calcium-sensitive protein in a highly cooperative way. We here show that this soluble protein, i.e. the modulator of photoreceptor guanylate cyclase, is a 26 kd protein. Reconstitution of the purified 26 kd protein with washed rod outer segment membranes containing guanylate cyclase revealed a 3- to 4-fold increase of cyclase activity when the free calcium concentration was lowered in the physiological range from 0.5 microM to 4 nM. Guanylate cyclase in whole rod outer segments was stimulated 10-fold in the same calcium range. The activation process in the reconstituted system was similar to the one in the native rod outer segment preparation, it showed a high cooperativity with a Hill coefficient n between 1.4 and 3.5. The half-maximal activation occurred between 110 and 220 nM free calcium. The molar ratio of the modulator to rhodopsin is 1:76 +/- 32. The protein is a calcium binding protein as detected with 45Ca autoradiography. Partial amino acid sequence analysis revealed a 60% homology to visinin from chicken cones.
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PMID:A 26 kd calcium binding protein from bovine rod outer segments as modulator of photoreceptor guanylate cyclase. 167 37

12-Hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) as well as several other fatty acid hydroperoxides are potent inhibitors of platelet activation. 12-HPETE but not 12-hydroxy-5,8,10,14-eicosatetraenoic acid blocks the U46619- and the thrombin-triggered aggregation of aspirin-treated platelets, dose dependently. 12-HPETE suppresses thromboxane production by inhibiting platelet cyclooxygenase and stimulates its own production by increasing lipoxygenase activity, although this effect does not explain the inhibitory activity of 12-HPETE during the initial phase of cell activation. The inhibitory effect is related to altered calcium homeostasis during platelet activation. 12-HPETE inhibits calcium release from intracellular stores and modifies the influx of extracellular calcium. The inhibitory effect on calcium mobilization is explained by activation of soluble guanylate cyclase. These inhibitory properties are shared by sodium nitroprusside, a compound known to activate soluble guanylate cyclase. Fatty acid hydroperoxides, especially 12-HPETE, produce a rapid and dose-dependent activation of soluble guanylate cyclase, using intact human platelets as a detection system. Activation of the enzyme shows a position isomer specificity, with 12-HPETE being the most potent activator. The generation of the labile lipoxygenase product 12-HPETE during platelet activation may modulate platelet reactivity by increasing cyclic GMP. This pathway may contribute to a physiological feedback mechanism to limit the size of a growing platelet plug.
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PMID:12-hydroperoxyeicosatetraenoic acid inhibits main platelet functions by activation of soluble guanylate cyclase. 167 88

CaCl2 inhibited ATP-stimulated guanylate cyclase activity, but had little effect on basal and atrial natriuretic factor-stimulated guanylate cyclase activity in rat lung membranes. LaCl3 had similar effects as CaCl2 on basal and stimulated guanylate cyclase activity. LiCl and other monovalent salts inhibited ATP-stimulated guanylate cyclase activity more than basal enzyme activity. However, atrial natriuretic factor somehow stabilized the enzyme against the inhibitory effect of LiCl. These results suggest that ATP and atrial natriuretic factor activate the enzyme through different mechanisms. Since the effect of calcium on guanylate cyclase activity is different from that of monovalent salts and can be mimicked by lanthanum, it may be mediated by a specific calcium binding site or binding protein.
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PMID:Calcium reveals different mechanisms of guanylate cyclase activation by atrial natriuretic factor and ATP in rat lung membranes. 167 90


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