Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human neutrophils were incubated with granulocyte-macrophage (GM)-CSF and examined for changes in second messenger systems. Twofold increases in cGMP but not cAMP were measured after 5 to 20 min with 100 U/ml GM-CSF. Guanylate cyclase activities in membrane and cytosol fractions were increased to the same extent whether measured in the presence of Mg2+ or Mn2+, or in the cytosol with Mg2+ + N-methyl-N'-nitro-N-nitroso-guanidine. Kinetic studies of the cytosol enzyme showed no changes in the Km values for Mg2+ and Mn2+dependent guanylate cyclase activities (0.91 and 0.022 mM, respectively), whereas Vm values were increased after treating intact cells with GM-CSF. Two peaks of guanylate cyclase activity were observed, one at 10 and another at 60 min after adding 100 U/ml GM-CSF, whereas only one peak at 5 min occurred with 1 U/ml. Adenylate cyclase activity was reduced by nearly 50% after adding 100 U/ml GM-CSF for 10 to 30 min. These effects were also seen in the presence of several hormonal and nonhormonal adenylate cyclase stimulators. In contrast, small increases in adenylate cyclase activity occurred after adding 1 U/ml GM-CSF. In experiments to examine the pathway of guanylate cyclase activation by GM-CSF, we observed no changes in inositol phosphates, intracellular calcium ion, or cytosolic protein kinase C. The augmentation of chemotactic peptide-induced superoxide production by GM-CSF concentrations, may be related to the effects of the higher levels of GM-CSF to stimulate late increases in guanylate cyclase or decreases in adenylate cyclase.
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PMID:Stimulation of guanylate cyclase activity and reduction of adenylate cyclase activity by granulocyte-macrophage colony-stimulating factor in human blood neutrophils. 289 92

We have isolated a 3.9-kbp-long cDNA and approximately 93 kbp long genomic DNA encoding a membrane guanylyl cyclase (designated OlGC1) from the medaka fish Oryzias latipes, and determined their nucleotide sequences. The open reading frame for the OlGC1 cDNA predicts a protein of 1,055 amino acids. Phylogenetic analysis indicates OlGC1 to be a medaka fish homolog of mammalian guanylyl cyclase B (GC-B), a member of the natriuretic peptide receptor family. Northern blot analysis demonstrated 3.9 kb OlGC1 transcripts in the eye and brain, while reverse transcription-polymerase chain reaction (RT-PCR) analysis showed OlGC1 transcripts in a number of adult peripheral organs as well as embryos during early stages of development. The OlGC1 gene consists of 22 exons with an exon/intron organization similar to that of the human and rat GC-A genes, except that OlGC1 has several very large introns. The OlGC1 gene has no apparent TATA box or CAAT box in the region 1.2 kbp upstream of the putative transcription initiation point, but several consensus sequences for cis-regulatory elements, including an NF-IL6-binding element, a shear stress responsive element, and multiple GM-CSF-binding elements, are present in that region.
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PMID:Genomic structure and expression of the medaka fish homolog of the mammalian guanylyl cyclase B. 1039 27

The signalling pathways mediating neutrophil spontaneous apoptosis are still largely unknown. We report that the indolocarbazole compound KT5823, a specific inhibitor of cGMP-dependent protein kinases (cGK), dose-dependently inhibited spontaneous apoptosis of neutrophils. At the concentration eliciting the maximum effect (8 microM), it decreased apoptosis from 72.42+/-12.79% to 45.86+/-7.22% (p=0.0002, n=6). Similarly, the isoquinoline sulfonamide compound H89, another cGK inhibitor, prevented neutrophil apoptosis. At the concentration eliciting the maximum effect (20 microM), it decreased apoptosis from 72.42+/-12.79% to 31.84+/-10.70% (p=0.0004, n=6). The maximum effect of KT5823 and H89 was comparable to that of GM-CSF and LPS, respectively. Moreover, YC-1, a soluble guanylate cyclase activator, and 4-([3',4',-(methylenedioxy)benzyl]amino)-6-methoxyquinazoline, a specific phosphodiesterase 5 inhibitor, enhanced neutrophil apoptosis, and their effect was antagonised by KT5823. Taken together, these observations highlight a new role of cGK as important mediators of neutrophil spontaneous apoptosis.
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PMID:Inhibition of cGMP-dependent protein kinases potently decreases neutrophil spontaneous apoptosis. 1227 Jan 21

The generation of toxic concentrations of nitric oxide by the inducible nitric oxide synthase expressed in microglia and other brain cell types is frequently invoked as a causative factor in neurodegeneration. Experiments were carried out on slice cultures of rat hippocampus to test this hypothesis. Exposure of the slices to bacterial lipopolysaccharide plus interferon-gamma led to a time-dependent expression of functional inducible nitric oxide synthase that was found only in microglia. Microglial activation by other means, such as physical damage, was not associated with inducible nitric oxide synthase expression. Damage and cell death in slices expressing inducible nitric oxide synthase was evaluated over a period of 6 days, but none was found. Consistent with this result, cGMP measurements indicated that the average local nitric oxide concentration remained in the low nanomolar range. When the microglial population was expanded to a density three-fold above normal by applying granulocyte-macrophage colony stimulating factor, however, lipopolysaccharide plus interferon-gamma provoked neurodegeneration that could be blocked by an inducible nitric oxide synthase inhibitor. The associated nitric oxide concentration in the slices was saturating for guanylyl cyclase-coupled nitric oxide receptors, signifying at least 10 nM. It is concluded that inducible nitric oxide synthase is expressed in microglia only in response to specific stimuli involving the innate immune system, and that the resulting level of nitric oxide in intact brain tissue is normally too low to inflict damage directly. Quantities of nitric oxide sufficient to contribute directly or indirectly to pathology could be produced should the density of microglia become high enough, although caution must be exercised in extrapolating this finding to the human brain in vivo.
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PMID:Pathological consequences of inducible nitric oxide synthase expression in hippocampal slice cultures. 1616 95

Colorectal cancer immunotherapy is limited by the paucity of available target antigens fulfilling the necessary criteria of tumor-specificity, sufficient immunogenicity and universal association with disease. A novel class of immune targets, cancer mucosa antigens (CMAs), whose expression normally is confined to mucosae but maintained during neoplastic transformation, promises to overcome these imitations, enjoying the advantage of immune compartmentalization, preventing autoimmune disease, while permitting therapeutic anti-tumor responses. Indeed, therapeutic immunization against the model CMA guanylyl cyclase c (GCC) extends survival in mouse models of established parenchymal colorectal cancer metastases with antitumor efficacy superior to currently available antigens. Here adjuvanation of therapeutic antitumor immunity to GCC was explored employing the cytokines IL-2 and GM-CSF in a mouse model of metastatic colorectal cancer. Combining plasmids expressing murine IL-2 or GM-CSF with recombinant viral vector immunization to GCC enhanced antitumor efficacy beyond viral vector immunization alone. These studies support the incorporation of IL-2 and GM-CSF in CMA-targeted immunization regimens for established colorectal cancer metastases.
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PMID:Cytokine adjuvanation of therapeutic anti-tumor immunity targeted to cancer mucosa antigens. 1995 76