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)

Primary cultures of anterior and intermediate pituitary tissues were monitored immunocytochemically for the presence of endocrine and nonendocrine cells and simultaneously tested for their ability to produce cyclic GMP in response to atrial natriuretic factor (ANF). Cells cultured for 3 days and 6 days, in which nonendocrine (vimentin-positive) cells were found to rapidly overgrow the endocrine cells, showed a dramatic elevation in cyclic GMP production stimulated by ANF, with maximum stimulation 300-700% that seen in 1-day cultured cells. Also, ANF-induced accumulation of cyclic GMP in an enriched population of vimentin-positive cells appeared to closely match that triggered in a 3-day culture of anterior pituitary cells, emphasizing the major role played by nonendocrine cells and their ability to synthesize cyclic GMP. In contrast, in the homogeneous population of tumor corticotrophs AtT-20, there was a close relationship between cyclic GMP formation and cell density. It thus appears that contamination of primary cultures of anterior and intermediate pituitary tissues by proliferating nonendocrine cells (mainly fibroblasts), in which ANF-induced accumulation of cyclic GMP may be confused with that of the very secretory cells, leads to overestimation and masking of guanylate cyclase activity of endocrine cells.
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PMID:Stimulation by atrial natriuretic factor of cyclic GMP production in cultured anterior and intermediate pituitary tissues: evidence for a major contribution of proliferating nonendocrine cells. 255 58

The effects of guanosine 3',5'-cyclic monophosphate (cGMP) on the secretory response of activated human neutrophils were investigated using LY-83583, an inhibitor of soluble guanylate cyclase, and L-arginine, the precursor of nitric oxide formation. A 30% release of myeloperoxidase (MPO) and lactoferrin (LF) from the primary and specific granules, respectively, was detected by enzyme-linked immunosorbent assay in adhered neutrophils stimulated with 0.1 microM N-formyl-methionyl-leucyl-phenylalanine (FMLP) or 20 microM A-23187. LY-83583 (100 microM) inhibited the release of both LF and MPO after stimulation with FMLP or A-23187. Conversely, preincubation of neutrophils with 0.5 mM L-arginine augmented the release of LF and MPO in FMLP- and A-23187-stimulated cells. Concurrent with the increase in the degranulation response was an elevation of cGMP levels in L-arginine-treated cells, while stimulated cGMP levels were reduced in LY-83583-treated cells. Furthermore, cGMP-dependent protein kinase (G-kinase) activity was reduced in LY-83583-treated cells, as determined by the delay in G-kinase translocation to intermediate filaments and the inhibition of vimentin phosphorylation. Degranulation, elevation of cGMP levels, and targeting of G-kinase were also dependent on the concentration of A-23187 or FMLP. These data suggest that activators of neutrophil degranulation mediate this response through a cGMP-dependent protein kinase mechanism.
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PMID:Regulation of human neutrophil degranulation by LY-83583 and L-arginine: role of cGMP-dependent protein kinase. 833 31

The distribution of nerves with the potential to synthesize nitric oxide was examined within the urinary bladder and proximal urethra of humans and guinea-pigs, using an antibody to nitric oxide synthase. Further experiments identified cells in which cGMP-immunoreactivity was induced following exposure to the nitric oxide donor, sodium nitroprusside. These cells represent the potential physiological targets of neuronally released nitric oxide, since activation of soluble guanylate cyclase, and a consequent rise in intracellular cGMP, mediate many of the effects of this transmitter. Nitric oxide synthase-immunoreactivity was widely distributed in the lower urinary tract. In guinea-pigs, 50-68% of all intrinsic vesical neurons expressed nitric oxide synthase-immunoreactivity, while in humans 72-96% of neurons in the wall of the bladder contained nitric oxide synthase. In both humans and guinea-pigs, varicose nitric oxide synthase-immunoreactive nerve terminals provided a moderate innervation to the detrusor muscle of the bladder body, and a denser innervation to the urethral muscle. Immunoreactive nerves also projected to the subepithelium and around blood vessels, but were rarely observed encircling intramural vesical ganglia. Following stimulation with sodium nitroprusside, smooth muscle cells of the urethra expressed strong cGMP-immunoreactivity, but detrusor muscle cells remained uniformly negative. Although the detrusor muscle fibres did not express cGMP, numerous interstitial cells throughout the bladder body demonstrated an intense induction of cGMP-immunoreactivity by sodium nitroprusside. These cells had long dendritic processes extending parallel to the smooth muscle fibres, and contained vimentin, an intermediate filament expressed by cells of mesenchymal origin. Other cell types in which sodium nitroprusside exposure induced cGMP-immunoreactivity were the uroepithelial cells, vascular smooth muscle cells and pericytes, and a small number of varicose nerve terminals. In the guinea-pig, a minor proportion (less than 10%) of intrinsic neurons in the wall of the bladder also expressed cGMP. No intrinsic neurons were observed in specimens of human bladder processed for cGMP immunohistochemistry. The results provide anatomical evidence that nitric oxide may function as a neurotransmitter in the lower urinary tract. Although nerves with the capacity to produce nitric oxide supply both the detrusor muscle and the urethra, distinct regional differences exist in the effects of nitric oxide on the induction of cGMP. If the nitric oxide-mediated induction of cGMP is a reliable indicator of the physiological responsiveness of a cell to nitric oxide, then smooth muscle cells appear to be the predominant targets of nitric oxide in the urethra, while in the bladder body, interstitial cells may serve this role. These findings support previous studies which have implicated nitric oxide as an inhibitory transmitter involved in the relaxation of the bladder neck. Our experiments further indicate that a number of cell types within the lower urinary tract could potentially mediate the effects of endogenously released nitric oxide.
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PMID:Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. 905 89

Two types of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified in different tissues. Type 1 has both oxidase and reductase activities interconverting cortisol and cortisone, whereas type 2 has only oxidase activity converting cortisol to cortisone. It has been proposed that placental 11 beta-HSD controls the passage of maternal glucocorticoids to the fetal circulation. However, little is known about the regulation of 11 beta-HSD in the human placenta and fetal membranes. We cultured human term placental trophoblast and chorionic trophoblast cells to examine effects of nitric oxide donors, sodium nitroprusside (SNP) and S-nitroso-N-acetyl penicillamine (SNAP), on the activity and messenger RNA (mRNA) expression of 11 beta-HSD. At 72 h of culture, placental trophoblast formed syncytial clumps that were cytokeratin positive and displayed mainly type 2 oxidase activity, although some type 1 reductase activity was detectable. Chorion preparations contain greater than 90% trophoblast cells as demonstrated by immunostaining for cytokeratin and less than 5% vimentin positive cells. Type 1 reductase activity predominated in the chorionic trophoblast cells with barely detectable type 1 or type 2 oxidase activity. Both SNP (1-400 microM) and SNAP (1 mM) inhibited placental 11 beta-HSD type 2 oxidase activity but not type 1 reductase activity either in placental or chorionic cells. An inhibitory effect on type 2 oxidase activity was reproduced in part by 8-bromo cGMP, blocked partially by the guanylate cyclase inhibitor LY83583 (1 microM), but not by an ADP-ribosylation inhibitor N, N'-hexamethylene-bis-acetamide (HMBG) (10 mM). SNP also suppressed the expression of type 2 mRNA in cultured placental trophoblast in a dose-dependent manner, and this effect was also blocked by LY83583. We conclude that human placental trophoblast possesses predominantly 11 beta-HSD type 2 oxidase activity, whereas chorionic cells possess mainly type 1 reductase activity under the culture conditions employed. Nitric oxide specifically attenuated 11 beta-HSD type 2 oxidase activity as well as its mRNA expression in the placental trophoblast. The effect was mediated at least partially through the cGMP pathway, although an alternative pathway other than ADP-ribosylation may exist.
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PMID:Differential regulation of 11 beta-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation. 934 22

In neutrophils activated to secrete with formyl-methionyl-leucyl-phenylalanine, intermediate filaments are phosphorylated transiently by cyclic guanosine monophosphate (cGMP)-dependent protein kinase (G-kinase). cGMP regulation of vimentin organization was investigated. During granule secretion, cGMP levels were elevated and intermediate filaments were transiently assembled at the pericortex to areas devoid of granules and microfilaments. Microtubule and microfilament inhibitors affected intermediate filament organization, granule secretion, and cGMP levels. Cytochalasin D and nocodazole caused intermediate filaments to assemble at the nucleus, rather than at the pericortex. cGMP levels were elevated in neutrophils by both inhibitors; however, with cytochalasin D, cGMP was elevated earlier and granule secretion was excessive. Nocodazole did not affect normal cGMP elevations, but specific granule secretion was delayed. LY83583, a guanylyl cyclase antagonist, inhibited granule secretion and intermediate filament organization, but not microtubule or microfilament organization. Intermediate filament assembly at the pericortex and secretion were partially restored by 8-bromo-cGMP in LY83583-treated neutrophils, suggesting that cGMP regulates these functions. G-kinase directly induced intermediate filament assembly in situ, and protein phosphatase 1 disassembled filaments. However, in intact cells stimulated with formyl-methionyl-leucyl-phenylalanine, intermediate filament assembly is focal and transient, suggesting that vimentin phosphorylation is compartmentalized. We propose that, in addition to changes in microfilament and microtubule organization, granule secretion is also accompanied by changes in intermediate filament organization, and that cGMP regulates vimentin filament organization via activation of G-kinase.
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PMID:Chemotactic peptide-induced changes of intermediate filament organization in neutrophils during granule secretion: role of cyclic guanosine monophosphate. 976 53

Previous studies have demonstrated that functional interaction between endothelin (ET)-1 and nitric oxide (NO) involves changes in Ca(2+) mobilization and cytoskeleton in human brain microvascular endothelial cells. The focus of this investigation was to examine the possible existence of analogous interplay between these vasoactive substances and elucidate their signal transduction pathways in human brain capillary endothelial cells. The results indicate that ET-1-stimulated Ca(2+) mobilization in these cells is dose-dependently inhibited by NOR-1 (an NO donor). This inhibition was prevented by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-CPT-cGMPS (an inhibitor of protein kinase G). Treatment of endothelial cells with 8-bromo-cGMP reduced ET-1-induced Ca(2+) mobilization in a manner similar to that observed with NOR-1 treatment. In addition, NOR-1 or cGMP reduced Ca(2+) mobilization induced by mastoparan (an activator of G protein), inositol 1,4,5-trisphosphate, or thapsigargin (an inhibitor of Ca(2+)-ATPase). Interestingly, alterations in endothelial cytoskeleton (actin and vimentin) were associated with these effects. The data indicate for the first time that the cGMP-dependent protein kinase colocalizes with actin. These changes were accompanied by altered levels of phosphorylated vasodilator-stimulated phosphoprotein, which were elevated in endothelial cells incubated with NOR-1 and significantly reduced by ODQ or Rp-8-CPT-cGMPS. The findings indicate a potential mechanism by which the functional interrelationship between ET-1 and NO plays a role in regulating capillary tone, microcirculation, and blood-brain barrier function.
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PMID:ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. 1252 47

Nitric oxide (NO) synthase (NOS) catalyzes the oxidation of L-arginine to NO. NO plays a crucial role in regulating various physiological functions, possibly including junction dynamics via its effects on cAMP and cGMP, which are known modulators of tight junction (TJ) dynamics. Although inducible NOS (iNOS) and endothelial NOS (eNOS) are found in the testis and have been implicated in the regulation of spermatogenesis, their role(s) in TJ dynamics, if any, is not known. When Sertoli cells were cultured at 0.5-1.2 x 10(6) cells/cm(2) on Matrigel-coated dishes or bicameral units, functional TJ barrier was formed when the barrier function was assessed by quantifying transepithelial electrical resistance across the cell epithelium. The assembly of the TJ barrier was shown to associate with a significant plummeting in the levels of iNOS and eNOS, seemingly suggesting that their presence by producing NO might perturb TJ assembly. To further confirm the role of NOS on the TJ barrier function in vitro, zinc (II) protoporphyrin-IX (ZnPP), an NOS inhibitor and a soluble guanylate cyclase inhibitor, was added to the Sertoli cell cultures during TJ assembly. Indeed, ZnPP was found to facilitate the assembly and maintenance of the Sertoli cell TJ barrier, possibly by inducing the production of TJ-associated proteins, such as occludin. Subsequent studies by immunoprecipitation and immunoblotting have shown that iNOS and eNOS are structurally linked to TJ-integral membrane proteins, such as occludin, and cytoskeletal proteins, such as actin, vimentin, and alpha-tubulin. When the cAMP and cGMP levels in these ZnPP-treated samples were quantified, a ZnPP-induced reduction of intracellular cGMP, but not cAMP, was indeed detected. Furthermore, 8-bromo-cGMP, a cell membrane-permeable analog of cGMP, could also perturb the TJ barrier dose dependently similar to the effects of 8-bromo-cAMP. KT-5823, a specific inhibitor of protein kinase G, was shown to facilitate the Sertoli cell TJ barrier assembly. Cytokines, such as TGF-beta and TNF-alpha, known to perturb the Sertoli cell TJ barrier, were also shown to stimulate Sertoli cell iNOS and eNOS expression dose dependently in vitro. Collectively, these results illustrate NOS is an important physiological regulator of TJ dynamics in the testis, exerting its effects via the NO/soluble guanylate cyclase/cGMP/protein kinase G signaling pathway.
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PMID:Regulation of Sertoli cell tight junction dynamics in the rat testis via the nitric oxide synthase/soluble guanylate cyclase/3',5'-cyclic guanosine monophosphate/protein kinase G signaling pathway: an in vitro study. 1281 May 68

The purpose of this study was to investigate the role of cyclic GMP (cGMP) in the effects of nitric oxide (NO) on urethral striated muscle and its involvement in contractile function. The localization of cGMP, neuronal NO synthase (nNOS), vimentin, and neuronal markers was assessed by immunofluorescence in the sheep and rat urethra and the expression of nNOS was determined in Western blots. Nerve-mediated contractile responses to electrical field stimulation (EFS) were recorded in the sheep urethra. The scant nitrergic innervation of the striated muscle layer suggests that autonomic control of its activity is unlikely. The striated fiber itself may be the source of high levels NO produced by sarcolemmal and/or cytosolic mu or alpha variant of nNOS. This endogenous NO may provoke high basal production of soluble guanylate cyclase (GC) dependent cGMP, mainly in non-NO producing muscle fibers, which is not further enhanced by NO donors. cGMP co-localizes with neurofilament and PGP 9.5 at muscle endplates. Modulators of the cGMP pathway did not affect nerve-mediated contractile activity induced by EFS, suggesting that cGMP is not a significant mediator of neuromuscular transmission. In addition, NO donors did increase the accumulation of cGMP in dense networks of vimentin immunoreactive interstitial cells of Cajal (ICC), whose function is not yet known. These data suggest that there is a strong but non-regulated production of cGMP under resting conditions, which does not seem to affect contractile function. Modulation of cholinergic neurotransmission by NO through cGMP-independent mechanisms cannot be discarded.
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PMID:Refractoriness of urethral striated muscle contractility to nitric oxide-dependent cyclic GMP production. 2036 65

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