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)

Atrial natriuretic peptide (ANP) regulates diverse physiological responses by binding to its specific guanylyl cyclase-A receptor (Npra) which synthesizes the intracellular second messenger cGMP. To understand the molecular mechanisms of cellular signaling of ANP, we have studied its effect on the enzymatic activity of overexpressed protein kinase C (PKC) in murine Leydig tumor (MA-10) cells which were transfected with PKC-alpha cDNA. Treatments with 12-O-tetradecanoylphorbol-13-acetate (TPA), angiotensin II (ANG II) and endothelin-1 (ET-1) stimulated the PKC activity by 4-5-fold in PKC-alpha cDNA transfected MA-10 cells. The pretreatment of PKC-alpha transfected cells with ANP significantly inhibited the TPA-, ANG II- and ET-1-stimulated PKC activity. The agonist-stimulated PKC activity was also inhibited in the presence of 8-bromo-cGMP, however, cAMP had no effect on stimulatory PKC activity. The exposure of cells to Npra- antagonist A71915, which blocks the production of cGMP, significantly reduced the inhibitory effect of ANP on agonist-stimulated PKC activity and accumulation of intracellular cGMP in MA-10 cells. Similarly, inhibition of cGMP-dependent protein kinase by KT5823, restored the stimulatory levels of PKC activity in the presence of ANP. These results provide direct evidence that ANP antagonizes the agonist-stimulated PKC activity in MA-10 cells, involving the specific receptor Npra, its second messenger cGMP and cGMP-dependent protein kinase. Together, these findings implicate that ANP may act as a negative mediator of 'cross-talk' between PKC-alpha and Npra signaling pathway in MA-10 cells.
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PMID:Stimulation of atrial natriuretic peptide receptor/guanylyl cyclase- A signaling pathway antagonizes the activation of protein kinase C-alpha in murine Leydig cells. 915 Feb 79

We have previously shown that atrial natriuretic peptide (ANP) is present in caveolae of in situ rat atrial myocytes. To investigate whether intracaveolar ANP of rat atrial myocytes exists within caveolae bound to type B ANP receptors (ANP-RB, a guanylyl cyclase), we have used confocal immunofluorescence microscopy applied to primary cultures of atrial myocytes from adult rats and to freshly dissociated rat atrial myocytes (not cultured). These experimental designs tested whether atrial myocyte ANP-RB colocalizes at the plasmalemma and elsewhere in the cell with the muscle-specific isoform of the caveolar coating protein caveolin-3, and with a fraction of cellular ANP. The experiments showed that cellular caveolin-3, a fraction of cellular ANP-RB, and a fraction of cellular ANP colocalize at the plasmalemma of cultured atrial myocytes and of freshly dissociated atrial myocytes. The observations support the hypothesis that in rat atrial myocytes, intracaveolar ANP is bound to ANP-RB, a protein whose cytosolic amino acid sequences are known to encode guanylyl cyclase activity. We suggest that among the (probably multiple) effects of the cGMP thus generated in the cytoplasmic microdomain underlying atrial myocyte caveolae may be the activation of cGMP-dependent protein kinase, which would thereby inhibit plasma membrane Ca2+ channel activity and contribute to a negative inotropic effect of ANP.
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PMID:Type B atrial natriuretic peptide receptor in cardiac myocyte caveolae. 920 Oct 31

Parallel fiber synapses onto Purkinje neurons in acute cerebellar slices undergo long-term depression (LTD) when presynaptic activity coincides with postsynaptic depolarization. These electrical inputs can be respectively replaced by nitric oxide (NO) and Ca2+ photolytically released inside the Purkinje neuron, showing that these two messengers are sufficient for LTD induction. NO acts via cGMP production because inhibitors of guanylate cyclase prevent LTD but can be circumvented by photoreleased cGMP combined with Ca2+ elevation. Three inhibitors of cGMP-dependent protein kinase, Rp-8Br-PET-cGMPS, KT5823, and a novel pseudosubstrate peptide, all block LTD. LTD induction permits <10 ms gap between NO release and Ca2+ elevation, whereas 200-300 ms is allowed between uncaged cGMP and Ca2+ increase. This surprising difference in timing precision can be explained either by tighter localization and faster decay of cGMP when generated by NO rather than uncaging, or by two independent coincidence detectors in series.
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PMID:Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. 920 68

Ca2+ changes induced by nitric oxide (NO.) were investigated in cultured human endothelial cells. Sodium nitroprusside (SNP) (1-100 mumol/L) and S-Nitroso-N-acetylpenicillamine (SNAP) (100 mumol/L) were used as NO. donors. The cytoplasmatic Ca2+ concentration was calculated using ratiometric FURA2 fluorescence measurements. Both NO. donors caused transient oscillatory Ca2+ changes, which were not detectable in the presence of oxyhemoglobin (50 mumol/L). Digital ratio imaging revealed initiation sites within cells where Ca2+ increases started spreading, which indicates that nonuniformly distributed targets might be involved in these reactions. Calcium was released from intracellular stores as indicated by experiments performed in Ca(2+)-free buffer. L-type Ca(2+)-channel blocker diltiazem (100 mumol/L) was not able to block these responses. NO.-induced Ca2+ release from intracellular stores caused capacitative Ca2+ entry. Both thapsigargin (1 mumol/L) and cyclopiazonic acid (10 mumol/L) inhibited the SNP response completely, whereas neither ryanodine (up to 100 mumol/L) nor dantrolene (100 mumol/L) was able to inhibit Ca2+ changes induced by SNP, indicating that primarily inositol 1,4,5-triphosphate (IP3)-dependent stores are released upon stimulation with NO.. A small inhibitory effect of ATP- and SNP-induced peak [Ca2+]i increase was measured in the presence of both caffeine (20 mmol/L) and procaine (1 mmol/L). Evidence is presented that cGMP is not involved in NO.-induced Ca2+ signals, as neither inhibitors of guanylate cyclase (methylene blue and LY 83583) nor cell permeant analogues of cGMP altered or simulated [Ca2+] changes. An inhibitor of cGMP-dependent protein kinase was also ineffective. We therefore propose that endothelial cells have specific targets proximal or at IP3 receptors to induce Ca2+ changes in endothelial cells stimulated with NO..
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PMID:Nitric oxide induces transient Ca2+ changes in endothelial cells independent of cGMP. 928 49

Relatively high concentrations of azathioprine had an inhibitory effect on interleukin 8 (IL-8)- or formyl-methionyl-leucyl-phenylalanine-activated (fMLP)-chemotaxis by human neutrophils. However, application of low concentrations of azathioprine in a concentration gradient gave a chemotactic stimulation to random migration. Stimulation of migration was maximal at a concentration of 5 microM azathioprine; at higher concentrations stimulation decreased again. The activating effect of azathioprine is located in the mercaptopurine moiety of the molecule, since mercaptopurine also stimulated neutrophil migration. In contrast to some other chemotactic agents such as fMLP and IL-8, an activating concentration (5 microM) of azathioprine did not cause an upregulation of CD11b expression on neutrophils in suspension. High concentrations of azathioprine (1 mM) inhibited CD11b expression of fMLP- or IL-8- activated neutrophils; the latter could explain the inhibitory effect of azathioprine. Azathioprine caused a transient stimulation of cGMP level; inhibitors of guanylate cyclase inhibited azathioprine-stimulated migration, suggesting that cGMP was associated with the stimulating effect of azathioprine on migration. Antagonists of cGMP-dependent protein kinase (G-kinase) strongly inhibited azathioprine-activated migration, indicating that the effect of azathioprine proceeds via G-kinase. The antagonists had only a marginal effect on inhibition of IL-8-activated chemotaxis by high concentrations of azathioprine, thus the G-kinase seems not to be of great importance on the inhibitory effect of azathioprine.
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PMID:A cyclic GMP- and G-kinase-dependent effect of azathioprine on migration by human neutrophils. 928 61

Relatively low concentrations of pentoxifylline caused a stimulation of random migration, while high concentrations inhibited chemotactic migration activated by formyl-methionyl-leucyl-phenylalanine (fMLP). The stimulating effect of pentoxyfylline was partly chemokinetic and partly chemotactic, and was dependent on extracellular calcium. Activation of migration by pentoxifylline was not dependent on the pore size of the micropore filter, indicating that the effect was not mediated by the ability of the drug to induce membrane deformability. Inhibitors of guanylate cyclase and antagonists of cGMP-dependent protein kinase (G-kinase) inhibited stimulation of migration by pentoxifylline. Pentoxyfylline caused a transient increase in cGMP level, while only high concentrations of pentoxifylline caused an increase in cyclic adenosine monophosphate (cAMP) level. It is suggested that the increase of migration is caused by cGMP and is mediated by a G-kinase, while the inhibition of migration at high concentrations of pentoxifylline is mediated by cAMP.
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PMID:The effect of pentoxifylline on human neutrophil migration: a possible role for cyclic nucleotides. 931 74

Previous studies indicated that the Leydig cells of the human testes show similarities to neuroendocrine cells. In this context, the local synthesis of two neuroactive signaling molecules, namely nitric oxide (NO) and C-type natriuretic peptide (CNP), both acting via the second messenger, cyclic guanosine monophosphate (cGMP), might be of physiological relevance. By immunoblotting, immunohistochemical analyses and affinity crosslinking experiments, respectively, the presence of soluble guanylate cyclase (sGC), the NO receptor, and of guanylate cyclase B (GC-B), representing the CNP receptor, was demonstrated in Leydig cells, seminiferous tubules and blood vessels of the human testis. Moreover, cGMP and its binding protein cGMP-dependent protein kinase type I (GK I) were found in these structures. The functional activity of the two receptors was proved by generation of cGMP in response to treatments with the NO donor, sodium nitroprusside (SNP), and with CNP, respectively. As indicated by immunohistochemical analyses and by treatments of cells with either SNP or CNP, human Leydig tumour cells and MA10 cells, representing a mouse Leydig tumour cell line, were found to be distinguished by a reduced expression of the receptors for NO and CNP. Furthermore, expression levels of the components of the two cGMP-generating systems were found to be widely unchanged in Leydig cells during different ontogenetic stages. Though cGMP has been shown to influence testosterone release, the constant developmental expression patterns of NO and CNP apparently independent of differences in androgen production, the down-regulation of their receptors in tumorous cells, and the presence of GK I, may point to additional autocrine functions of these factors and of cGMP in Leydig cells. Moreover, possible paracrine actions of NO and CNP may include relaxation of seminiferous tubules and blood vessels in order to modulate sperm transport and testicular blood flow, respectively. These findings suggest that Leydig cell-derived factors may exert activities different from or in addition to those involved in the regulation of testosterone production.
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PMID:New aspects of Leydig cell function. 936 77

Nitric oxide (NO) is produced by the enzyme nitric oxide synthase (NOS) and has been implicated in inter- and intracellular communication in the nervous system. The present study was undertaken to assess the effects of sodium nitroprusside (SNP) and hydroxylamine (HOA), NO donors, on a dopamine (DA)-induced K+ current in identified Aplysia neurons using voltage-clamp and pressure ejection techniques. Bath-applied SNP (10-25 microM) reduced the DA-induced K+ current without affecting the resting membrane conductance and holding current. The DA-induced K+ current also was inhibited by the focal application of 200 microM HOA to the neuron somata. The DA-induced K+ current suppressing effects of SNP and HOA are completely reversible. Pretreatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microM), a specific inhibitor of NO-stimulated guanylate cyclase, and hemoglobin (50 microM), a nitric oxide scavenger, decreased the SNP-induced inhibition of the DA-induced current. In contrast, intracellular injection of 1 mM guanosine 3',5'-cyclic monophosphate (cGMP) or bath-applied 3-isobutyl-1-methylxanthine (IBMX; 50 microM), a non-specific phosphodiesterase inhibitor, inhibited the DA-induced current, mimicking the effect of the NO donors. These results demonstrate that SNP and HOA inhibit the DA-induced K+ current and that the mechanism of NO inhibition of the DA-induced current involves cGMP-dependent protein kinase.
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PMID:Nitric oxide inhibits the dopamine-induced K+ current via guanylate cyclase in Aplysia neurons. 936 30

Nitric oxide is produced by nitric oxide synthase enzymes, which cleave the amino acid L-arginine to form nitric oxide and the amino acid L-citrulline. Many of the biologic actions of nitric oxide occur because nitric oxide activates guanylate cyclase, which in turn synthesizes a second-messenger molecule, cyclic guanosine 3',5'-monophosphate (cGMP). The increased concentration of cGMP activates cGMP-dependent protein kinase, reducing intracellular concentrations of calcium and relaxing smooth muscle. Nitric oxide also has many important effects that may not be mediated through increases of pulmonary cGMP activity. These include the ability to scavenge oxygen free radicals, reduce oxygen toxicity, and inhibit platelet and leukocyte aggregation. Nitric oxide is metabolized and excreted via a number of diverse pathways that may modify the toxicity of the molecule.
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PMID:The biologic basis for inhaled nitric oxide. 939 Sep 16

Considerable controversy exists in the literature with regard to the nature of the agent mediating the biological effects of nitroxyl (NO-) donors. Here it is demonstrated that Angeli's salt (AS), a generator of NO-, enhanced human neutrophil migration. Under aerobic conditions, AS was converted to peroxynitrite to a small extent. However, using methionine, a scavenger of peroxynitrite, it was shown that peroxynitrite was not involved in AS-induced migration. AS equally enhanced human neutrophil migration under aerobic and anaerobic conditions, which strongly suggests that extracellular conversion of NO- to .NO by oxygen was not required. Furthermore, metHb and L-cysteine, which react more readily with NO- than with .NO, inhibited AS-induced migration, whereas the response towards gaseous .NO remained unaffected. AS induced an increase in the intracellular level of cGMP, although the curves for migration and cGMP level appeared to be slightly different in their concentration dependence. An inhibitor of soluble guanylate cyclase and antagonists of cGMP-dependent protein kinase had a more pronounced inhibitory effect on .NO-induced migration than on AS-induced migration. This suggests that the cGMP signalling cascade is partially, but not solely, responsible for AS-induced migration. As it has been demonstrated that soluble guanylate cyclase can only be activated by .NO, and not by NO-, these data indicate that NO- is at least partly converted intracellularly to .NO.
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PMID:Intracellular but not extracellular conversion of nitroxyl anion into nitric oxide leads to stimulation of human neutrophil migration. 948 Aug 81


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