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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of aging on the ATP-induced relaxation of rat thoracic aorta was examined. Haemoglobin, methylene blue and NG-nitro L-arginine, and removal of the endothelium inhibited or reversed the relaxation induced by ATP. The relaxant response of the aorta to ATP was greatest in the preparations from 4-week-old rats. As the age of rats increased to 45 and 105 weeks, the concentration-response curve for ATP was shifted to the right with reduction of maximal relaxation. ATP elevated cyclic GMP levels. This action was endothelium-dependent and inhibited by methylene blue, haemoglobin and NG-nitro L-arginine. With an increase in age of the rats from 4 weeks to 45 weeks, ATP-stimulated cyclic GMP production was attenuated, and in the aorta from 105-week-old rats cyclic GMP level was no longer elevated by ATP. In contrast to the age-associated marked change in cyclic GMP levels, cyclic AMP production was not affected by aging. It is suggested that age-related changes in ATP-induced relaxation and cyclic GMP formation occur mainly at the level of the vascular smooth muscle. Alterations in soluble guanylate cyclase, at step(s) distal to the guanylate cyclase, or in cyclic GMP-phosphodiesterase might contribute.
...
PMID:Possible association of decrease of ATP-induced vascular relaxation with reduction of cyclic GMP during aging. 166 32

Nitric oxide (NO) formation from L-arginine and subsequent activation of a soluble guanylate cyclase accounts for the effect of the endothelium derived relaxing factor (EDRF). Cyclic GMP produced in smooth muscle cells induces relaxation through a mechanism which involves cyclic GMP kinase, but has not yet been entirely elucidated. Experiments with specific inhibitors of the different cyclic nucleotide phosphodiesterases (PDEs) suggest that a cyclic GMP-inhibited PDE which selectively hydrolyzes cyclic AMP, called PDE III, might also be involved in the relaxing mechanism of cyclic GMP. In arteries removed from endotoxemic rats or exposed to E. coli endotoxin, an extra-endothelial production of NO or a NO-like relaxing factor is induced in smooth muscle cells. Evidence that this phenomenon may be important in endotoxin shock is provided by experiments in which vascular reactivity is restored to control level by inhibitors of NO production in endotoxemic rats. These findings show that the L-arginine-NO pathway and cyclic GMP play a major role in regulating vascular contractility in physiological and pathological conditions.
...
PMID:The L-arginine-NO pathway and cyclic GMP in the vessel wall. 166 67

1. The effects of selective inhibitors of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1 microM) precontracted rat aortic rings, with and without functional endothelium. 2. Four PDE forms were isolated by DEAE-sephacel chromatography from endothelium-denuded rat aorta: a calmodulin-activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP-specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I. 3. The PDE III inhibitors caused endothelium-independent relaxations of rat aortic rings with the following EC50 values (microM concentration producing 50% relaxation): LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither NG-monomethyl-L-arginine (L-NMMA, 300 microM), an inhibitor of the L-arginine-NO pathway, nor L-arginine (1 mM) modified the effect of PDE III inhibitors. However, methylene blue (10 microM) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930. 4. The specific PDE IV and PDE V inhibitors both produced endothelium-dependent relaxations which were inhibited by L-NMMA and by methylene blue (10 microM). In the presence of L-NMMA, relaxation was restored by subsequent addition of L-arginine. 5. The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium-denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC5o values 1.7 and 12 microM, respectively) or SNP (EC50 values 12.3 and 124 microM, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7 microM and for rolipram: 7, 13, 7 and 1.2 microM). 6. These results indicate that the relaxant effects of inhibitors of the cyclic AMP-specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP-mediated relaxation, possibly through the inhibition of the cyclic GMP-inhibited PDE III.
...
PMID:Endothelium-dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors. 166 41

Dictyostelium cells use extracellular cyclic AMP both as a chemoattractant and as a morphogen inducing cell-type-specific gene expression. Cyclic AMP binds to surface receptors, activates one or more G-proteins, and stimulates adenylate cyclase, guanylate cyclase and phosphoinositidase C. Mutant fgdC showed aberrant chemotaxis, and was devoid of cyclic AMP-induced gene expression and differentiation. Both the receptor- and G-protein-mediated stimulation of adenylate cyclase and guanylate cyclase were unaltered in mutant fgdC as compared to wild-type cells. In wild-type cells phosphoinositidase C was activated about twofold by the cyclic AMP receptor. In mutant fgdC cells, however, the enzyme was inhibited by about 60%. These results suggest that phosphoinositidase C is regulated by a receptor-operated activation/inhibition switch that is defective in mutant fgdC. We conclude that activation of phosphoinositidase C is essential for Dictyostelium development.
...
PMID:Abberant chemotaxis and differentiation in Dictyostelium mutant fgdC with a defective regulation of receptor-stimulated phosphoinositidase C. 166 62

Atrial natriuretic peptide (ANP) binds to a transmembrane receptor having intrinsic guanylyl cyclase activity; this receptor has been designated GC-A. Binding of ANP to GC-A stimulates its catalytic activity, resulting in increased production of the second messenger, cyclic GMP. Here we show that GC-A can be expressed in insect cells using a recombinant baculovirus and that the expressed protein retained its abilities to bind ANP and to function as an ANP-activated guanylyl cyclase. In addition, GC-A produced in insect cells was absolutely dependent on the presence of adenine nucleotides for activation by ANP. Millimolar concentrations of ATP were required for optimal activation. The relative potencies of various nucleotides for activation was adenosine 5'-O-(thiotriphosphate) greater than ATP greater than ADP, adenosine 5'-(beta, gamma-imino)triphosphate greater than ADP beta S. AMP had no effect. These studies suggest that binding of an adenine nucleotide, most likely to the protein kinase-like domain of GC-A, is absolutely required for ANP activation. Regulation of guanylyl cyclase activation by adenine nucleotides represents a novel mechanism for the modulation of signal transduction, possibly analogous in some respects to the role of guanine nucleotides and G proteins in the regulation of adenylyl cyclase activity.
...
PMID:Adenine nucleotides are required for activation of rat atrial natriuretic peptide receptor/guanylyl cyclase expressed in a baculovirus system. 167 58

The purine metabolites inosine and adenosine selectively increase the catecholamine, but not the acetylcholine production in cultured chick superior cervical ganglion neurons via an as yet unknown intracellular pathway. In order to elucidate some of the molecular events involved in this differential regulation of neurotransmitter production by purines, the SCG neurons were cultured in the presence of cyclic nucleotide analogs and activators of adenylate and guanylate cyclase. Neither 8-bromo-cyclic AMP (8-Br-cAMP), 8-bromo-cyclic GMP (8-Br-cGMP), or forskolin, an activator of adenylate cyclase, could mimic the effect of inosine, i.e. differentially increase catecholamine production. Sodium nitroprusside, an activator of guanylate cyclase, however, has a strong potentiating action on the effect of inosine. The noradrenergic properties of chick sympathetic neurons may thus be differentially modulated by a cGMP-dependent pathway.
...
PMID:Catecholaminergic traits of chick sympathetic neurons may be differentially regulated by a cGMP-dependent pathway. 167 90

Binding of cyclic AMP (cAMP) to the cell surface receptor induces a transient activation of guanylate cyclase in Dictyostelium discoideum. A frigid mutant (HC85) which lacks G alpha 2, a guanine nucleotide binding protein, does not respond to cAMP. We found that 2,3-dimercapto-1-propanol (BAL) induced a continuous activation both in the frigid and in its parents. Therefore, the BAL-induced continuous activation of guanylate cyclase is independent of G alpha 2. We also found that cAMP enhanced the BAL-induced continuous activation in the frigid mutant. This result suggests that an unidentified signal transduction mechanism from the cAMP-receptor besides the one involving G alpha 2 plays a role in the enhancement of activation. Lastly, we found that the BAL-induced continuous activation was terminated by cAMP in the parental strain, but not in the frigid mutant. Therefore, the cAMP-induced suppression on the BAL-induced continuous activation is mediated through G alpha 2.
...
PMID:Regulation of guanylate cyclase by a guanine nucleotide binding protein, G alpha 2, in Dictyostelium discoideum. 167 66

Light activation of cyclic GMP hydrolysis in rod outer segments is mediated by a G-protein which is active in the GTP-bound form. Substitution of GTP with a nonhydrolyzable GTP analogue is thought to leave the G-protein in a persistently activated state, thereby prolonging the hydrolysis of cyclic GMP. Restoration of cyclic GMP concentration in the cell also depends upon GTP since it is the substrate for guanylate cyclase, but little is known about the effects of GTP analogues on this enzyme. We report here the effects of the analogues of GTP and ATP as inhibitors and substrates of rod disk membrane guanylate cyclase. The rate of cyclic GMP synthesis from GTP in rod disk membranes was about 50 pmol min-1 (nmol of rhodopsin)-1. Analogues of GTP and adenine nucleotides competitively inhibited the cyclase activity. The order of inhibition, with magnesium as metal cofactor, was ATP greater than GMP-PNP greater than AMP-PNP approximately GTP-gamma-S; with manganese, AMP-PNP was more inhibitory than GTP-gamma-S. The inhibition constants, with magnesium as cofactor, were 0.65-2.0 mM for GTP-gamma-S, 0.4-0.8 mM for GMP-PNP, 1.5-2.3 mM for AMP-PNP, and 0.07-0.2 mM for ATP. The fraction of cyclase activity inhibited by analogues was similar at 1 and 0.03 microM calcium. Besides inhibition of cyclase, the analogues also served as its substrates. GTP-gamma-S substituted GTP with about 85% efficiency while GMP-PNP and ATP were about 5 and 7% as efficient, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Interactions of nucleotide analogues with rod outer segment guanylate cyclase. 167 98

We characterized in membranes from the human neuroblastoma cell line NB-OK-1, an ANP-R1 receptor (Mr 130 kDa) for the atrial natriuretic peptide (ANP). This receptor recognized biologically active forms of ANP with high affinity but showed no affinity for truncated ANP forms. It was functional in that binding correlated with guanylate cyclase activation (a 2-fold increase in Vmax) with the following rank order of potency: rat ANP-(99-126) greater than human ANP-(99-126) greater than human ANP-(102-126) greater than porcine BNP (brain natriuretic peptide). The enzyme required free Mn2+ in addition to the Mn-GTP substrate (Km of about 0.3 mM for both basal and ANP-stimulated activity). In the presence of dithiothreitol, the dose-response curve of guanylate cyclase activation was shifted rightward by a factor of 30. ANP-R1 receptors were upregulated through protein synthesis in cells exposed to 1 mM carbamylcholine or 1 mM dibutyryl cyclic AMP for 8-24 h (ANP was ineffective).
...
PMID:Characterization and regulation of atrial natriuretic peptide (ANP)-R1 receptors in the human neuroblastoma cell line NB-OK-1. 168 Jul 22

1. The vasorelaxant effects of FK409, a new nitrovasodilator synthesized from a microbial product, were compared with those of nitroglycerin in isolated coronary artery rings of the dog contracted with U46619 (10(-7) M). 2. FK409 (10(-11)-10(-5) M) and nitroglycerin (10(-9)-10(-4) M) each produced a concentration-dependent relaxation. Comparison of EC50 values showed that FK409 was about 25 times more potent than nitroglycerin. 3. Submaximum concentrations of nitroglycerin (10(-6) M) and FK409 (3 x 10(-8) M) elevated guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, effects associated with vasorelaxation. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 4. The concentration-relaxation curves for nitroglycerin and FK409 were shifted to the right by methylene blue (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of soluble guanylate cyclase, and to the left by M&B22,948 (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of cyclic GMP phosphodiesterase. 5. After exposure of coronary arteries to the maximally-effective concentration of nitroglycerin (10(-4) M), the mean EC50 value of FK409 did not change significantly, although that of nitroglycerin increased about 60 fold. After exposure to the maximally-effective concentration of FK409 (10(-5) M), the mean EC50 value of FK409 increased about 6 fold and that of nitroglycerin about 11 fold. 6. These results suggest that the vasorelaxant effect of FK409, like that of nitroglycerin, is due to activation of soluble guanylate cyclase and a resultant increase in intracellular cyclic GMP. However, compared with nitroglycerin, there was less self-tolerance to the relaxant effects of FK409 and relatively little cross-tolerance between the two agents.
...
PMID:Comparison of the effects of the novel vasodilator FK409 with those of nitroglycerin in isolated coronary artery of the dog. 168 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---