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)

We studied the effects and the mechanism of action of the cyclic GMP-lowering substance 6-anilino-5,8-quinolinedione (LY 83583) on cyclic GMP-mediated inhibition of platelet function. The activation of washed human platelets by thrombin was counteracted by 8-bromo-cyclic GMP and the direct activators of soluble guanylate cyclase, sodium nitroprusside and endothelium-derived relaxant factor (EDRF = nitric oxide). LY 83583 significantly antagonized the inhibitory effect of sodium nitroprusside and EDRF, but not that of 8-bromo-cyclic GMP, on thrombin-induced aggregation, ATP-release, adhesion to native endothelial cells and increase in concentration of free intracellular calcium ions. In accordance, increases in intracellular cyclic GMP by sodium nitroprusside and EDRF were attenuated by LY 83583. The inhibition of cyclic GMP-mediated effects on platelets by LY 83583 could be related to inhibition of platelet soluble guanylate cyclase, as the activation of the purified enzyme from platelets by sodium nitroprusside was directly inhibited by LY 83583. This effect of LY 83583 was attenuated in the presence of superoxide dismutase. Our findings support the hypothesis that sodium nitroprusside and EDRF inhibit platelet activation by stimulation of soluble guanylate cyclase via nitric oxide. Consequently, inhibition of nitric oxide-induced cyclic GMP formation by LY 83583, which may act by intracellular generation of superoxide anions, facilitates platelet activation.
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PMID:LY 83583 (6-anilino-5,8-quinolinedione) blocks nitrovasodilator-induced cyclic GMP increases and inhibition of platelet activation. 255 29

Various stimulants of the release of EDRF (endothelium-derived relaxing factor) increased intracellular cGMP levels in bovine aortic endothelial cells. ATP was the most effective compound tested, increasing cGMP 7-fold, followed by the calcium ionophore, A23187 (4.8-fold), and bradykinin (4.0-fold). The EC50 values were similar to those obtained when EDRF release was measured with the bioassay technique, which suggests a stimulation of endothelial guanylate cyclase by EDRF. The direct acting stimulants of soluble guanylate cyclase, sodium nitroprusside and SIN-1 (3-morpholino-sydnonimine), also increased the cGMP content of endothelial cells by 9.4 and 7.2 times, respectively. The effects of both groups of stimulants on cGMP levels were antagonized by the lipoxygenase inhibitor, nordihydroguaiaretic acid, and by the radical scavenger, phenylbutylnitrone, whereas gossypol or canavanine only antagonized the EDRF-induced effect on endothelial cGMP levels. Bradykinin, ATP and A23187 also increased the uptake of 45CaCl2 into endothelial cells but since the complete removal of extracellular Ca2+ or blockade of Ca2+ transport by LaCl3 did not affect the ability of these compounds to elevate cGMP levels, the formation of EDRF appears not to be triggered by an influx of extracellular calcium. This study provides evidence that EDRF stimulators enhance cGMP levels in endothelial cells, probably due to a direct activation of guanylate cyclase by EDRF.
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PMID:Effect of calcium on endothelium-derived relaxing factor formation and cGMP levels in endothelial cells. 255 53

We have characterized a magnesium-dependent guanylate cyclase in homogenates of Dictyostelium discoideum cells. 1) The enzyme shows an up to 4-fold higher cGMP synthesis in the presence of GTP analogues with half-maximal activation at about 1 microM guanosine 5'-O-(3-thio)triphosphate (GTP gamma S) or 100 microM guanosine 5'-(beta, gamma-imido)triphosphate; little or no stimulation was observed with GTP, guanosine mono- and diphosphates or with adenine nucleotides, with the exception of the ATP analogue adenosine 5'-(beta, gamma-imido)triphosphate. 2) Both basal and GTP gamma S-stimulated guanylate cyclase activity were rapidly lost from homogenates as was the ability of GTP gamma S to stimulate the enzyme after cell lysis. 3) Inclusion of 25 microM GTP gamma S during cell lysis reduced the KM for GTP from 340 to 85 microM and increased the Vmax from 120 to 255 pmol/min.mg protein, as assayed in homogenates 90 s after cell lysis. 4) Besides acting as an activator, GTP gamma S was also a substrate for the enzyme with a KM = 120 microM and a Vmax = 115 pmol/min.mg protein. 5) GTP gamma S-stimulated, Mg2+-dependent guanylate cyclase was inhibited by submicromolar concentrations of Ca2+ ions, and by inositol 1,4,5-trisphosphate in the absence of Ca2+ chelators. 6) Guanylate cyclase activity was detected in both supernatant and pellet fractions after 1 min centrifugation at 10,000 x g; however, only sedimentable enzyme was stimulated by GTP gamma S. We suggest that the Mg2+-dependent guanylate cyclase identified represents the enzyme that in intact cells is regulated via cell surface receptors, and we propose that guanine nucleotides are allosteric activators of this enzyme and that Ca2+ ions play a role in the maintenance of the enzyme in its basal state.
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PMID:Regulatory properties of magnesium-dependent guanylate cyclase in Dictyostelium discoideum membranes. 256 93

The effects of alpha-rat atrial natriuretic peptide (alpha-rANP) and sodium nitroprusside on the activity of rat lung particulate guanylate cyclase were examined. The particulate guanylate cyclase in partially purified rat lung membranes was stimulated by both alpha-rANP and nitroprusside. The effects of alpha-rANP and nitroprusside were, however, not additive. Diamide and N-ethylmaleimide almost completely abolished the nitroprusside-mediated stimulation, while they had only moderate effects on the alpha-rANP-mediated stimulation of the enzyme activity. ATP potentiated the enzyme stimulation by alpha-rANP, whereas it had no effect on the nitroprusside-mediated stimulation. These findings suggest that the stimulation of lung particulate guanylate cyclase activity by alpha-rANP and nitroprusside is mediated by different mechanisms.
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PMID:Differential stimulation of rat lung particulate guanylate cyclase activity by atrial natriuretic peptide and sodium nitroprusside. 256 87

PGE2 and PGA2 incubated for 30 min at 25 degrees C with microsomal membranes isolated from Walker-256 tumour, in the presence of 50 microM indomethacin increase the lipid fluidity estimated by steady-state fluorescence anisotropy [(r0/r)-1]-1, using 1,6-diphenyl-1,3,5-hexatriene (DPH) as probe. The microsomal preparations of Walker-256 tumour contained calcium-stimulated and magnesium-dependent ATPase as well as calmoduling-dependent guanylate cyclese activities. A considerable decrease (approx. 65%) in the activity of the Ca2+-stimulated ATPase was observed when preparations were treated with 10 microM PGE2 and PGA2. A dramatic gradual decrease of the calmodulin-dependent guanylate cyclase activity was also observed at different concentrations of PGE2 and PGA2 (0.25-10 microM). The ATP-dependent uptake of calcium was reduced by approximately 60% in microsomal membranes treated with PGE2 and PGA2. The allosteric properties of Ca2+-stimulated ATPase by Na+, and of guanylate cyclase by Mn.GTP (as reflected by changes in the Hill coefficients, h) were modulated by PGE2 and PGA2. The apparent cooperativity of the Ca2+-ATPase (h + 1.73 +/- 0.21) in control membranes was abolished (h + 1.1 +/- 0.11 and h = 0.9 +/- 0.09) in membranes treated by PGE2 and PGA2 (10 microM), while the allosteric stimulation of guanylate cyclase by Mn.GTP was reduced from h = 2.78 +/- 0.24 in control membranes to h = 1.92 +/- 0.16 and h = 1.73 +/- 0.15 in membranes treated by PGE2 and PGA2 (10 microM), respectively, suggesting that the physical state of Ca2+-stimulated ATPase and guanylate cyclase lipid microenvironments changed from a gel phase to a liquid-crystalline phase. In conclusion, it is suggested that PGE2 and PGA2 promote a phase separation in Walker-256 tumour microsomal membranes. This may be relevant to the Ca2+-calmodulin system and tumour growth inhibition.
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PMID:PGE2 and PGA2 affect the allosteric properties and the activities of calmodulin-dependent guanylate cyclase and Ca2+-stimulated ATPase of Walker-256 tumour microsomal membranes. 256 56

Sodium nitroprusside, an activator of the soluble guanylate cyclase, inhibits the intracellular Ca2+ mobilization, ATP secretion and aggregation of human platelets evoked by fluoroaluminate. Similar results are obtained with 8-bromo-cyclic GMP (8-Br-cGMP). Both nitroprusside and 8-Br-cGMP inhibit the protein kinase C-dependent phosphorylation of the 47 and 20 kDa proteins induced by fluoroaluminate, but not by the protein kinase C activators phorbol ester and diacylglycerol. Since fluoroaluminate interacts directly with a G protein, the present results suggest that the cGMP interferes with platelet activation at the level of G protein-phospholipase C.
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PMID:Cyclic GMP and nitroprusside inhibit the activation of human platelets by fluoroaluminate. 257 92

Recent progress in understanding phototransduction has come primarily from studies on cell-free systems. To investigate the transduction process under physiological conditions, a fully functional preparation of retinal rod outer segments without attached inner segments was developed that allows electrical recording of light-sensitive current during intracellular dialysis with defined solutions. No light-sensitive current is recorded from detached outer segments dialyzed with nucleotide-free solutions, whereas cells detached from the retina into Ringer's solution containing 3-isobutyl-1-methyl-xanthine (a phosphodiesterase inhibitor) develop a light-sensitive inward dark current. This indicates that there is a basal level of cGMP-specific phosphodiesterase activity in the dark. Detached outer segments dialyzed with greater than or equal to 20 microM cGMP rapidly develop a light-suppressible current. A current of similar magnitude is generated more slowly during dialysis with a 50-fold greater concentration of GTP. Apparently, cGMP can be synthesized from GTP by guanylate cyclase in the outer segment. Cells dialyzed with cGMP alone show a reduced light sensitivity that is restored to normal by addition of 20 microM GTP. This action of GTP is antagonized by guanosine 5'-[beta-thio]diphosphate. These findings are in good agreement with biochemical evidence indicating that a GTP-binding protein (transducin) plays a pivotal role in the generation of responses to light. The recovery of photocurrent following a brief flash is delayed or abolished by dialysis with solutions that lack ATP or contain guanosine 5'-[gamma-thio]triphosphate, a nonhydrolyzable GTP analog. These results support the view that both GTP hydrolysis by activated transducin and ATP-dependent phosphorylation of a rhodopsin photoproduct are necessary for termination of the transduction process.
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PMID:Intracellular biochemical manipulation of phototransduction in detached rod outer segments. 282 76

The review deals with the critical analysis of the recent publications showing an important role of the endothelium in the mechanism of vasodilation caused by endogenous agents (acetylcholine, bradykinin, substance P, ATP, histamine, thrombin) and pharmacological agents (clonidine, hydralazine, mellitin, calcium ionophore A 23187). The mechanism of the endothelium-dependent vasodilatation is based on the release of the endothelium-derived relaxant factor (EDRF). In 1987-1988 it was shown that in some cases EDRF is NO. The experimental evidence suggests that EDRF (NO) may directly activate guanylate cyclase that results in vascular smooth muscle relaxation due to cAMP accumulation. The possible physiological and pathophysiological significance of the endothelium-dependent vascular responses is discussed.
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PMID:[The pharmacology of endothelium-dependent vascular reactions]. 285 Feb 22

Resact, a peptide obtained from eggs, causes a change in the Mr, and a loss of 32P from a plasma membrane protein identified as guanylate cyclase. Here, a resact analog (125I-[Tyr1, Ser8] resact) was synthesized and shown to bind to isolated sperm membranes. Resact, but not speract, competed with the radiolabeled ligand for binding. When membranes were prepared under appropriate conditions, guanylate cyclase remained at Mr 160,000; the incubation of membranes with gamma-32P-ATP resulted in the formation of 32P-labeled guanylate cyclase. The addition of resact to the membranes caused a shift in the Mr, a complete loss of 32P, and a 70% reduction in guanylate cyclase activity within 1 min; resact had an ED 50 at 100 nM concentration. Speract failed to cause any of these effects. This represents the first demonstration of receptor-mediated responses of isolated sperm membranes identical to those seen in the intact cell.
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PMID:Retention of a functional resact receptor in isolated sperm plasma membranes. 287 Aug 13

The metabolism of photoreceptor cGMP and the relationship of its light-sensitive regulation to rhodopsin photoisomerization and to the photoreceptor electrical response was examined in isolated, intact rabbit retinas. The dynamics of cGMP metabolism were assessed by measuring the rate of 18O incorporation from 18O-water into the alpha-phosphoryls of the guanine nucleotides. The photoreceptor electrical response was determined by measuring the aspartate-isolated mass receptor potential. Basal cGMP flux in dark-adapted retinas was 33 pmol cGMP X mg protein-1 X s-1 which translates into a metabolic rate in the rod outer segment (ROS) of 1.7 mM/min in ATP equivalents. Photic stimulation increased this flux as much as 4.5-fold. With continuous illumination, increasing intensity caused increments in cGMP metabolic flux to a maximum of 4.5-fold, with corresponding increases in the electrical response over the same 3-log unit intensity range. Tight coupling between activation of guanylate cyclase and phosphodiesterase was indicated by either no changes in cGMP steady state concentrations or relatively small fluctuations represented by increases of 50% at lower light intensities and a 12% decrease at one of the highest intensities. A stoichiometry of about 10,000 molecules of cGMP generated and hydrolyzed per photon absorbed was calculated for the lowest light intensity when the increment in cGMP metabolic flux per photon was maximal. Flashing light caused an increase in flux in proportion to frequency up to 1 Hz and a nearly proportional increase in the voltage time integral of the electrical response up to 0.5 Hz. This indicates that the temporal resolution, or "on"/"off" rate, of the cGMP metabolic response was as fast or faster than the temporal resolution of the electrical response. The concentration of cGMP remained relatively stable in spite of the marked acceleration of cGMP flux that occurred over the 32-fold range of frequencies tested. Taken together these results show that the light-accelerated rate of cGMP synthesis tightly coupled to hydrolysis becomes a primary energy-utilizing system in the photoreceptor and represents a response that fulfills certain of the fundamental criteria required of a metabolic event playing an essential role in phototransduction.
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PMID:Light-induced increases in cGMP metabolic flux correspond with electrical responses of photoreceptors. 287 93


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