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)

Previously, we showed that 5-norbornene-2,2-dimethanol (5-NBene-2,2-DM) is an effective inducer of melanogenesis in cultured cells and guinea-pig skin [Brown et al. (1998) J. Invest. Dermatol., 110:428-437]. This study shows that 2,3-cis/exo-pinanediol (2,3-cs/ex-PinD) is a more effective inducer of melanogenesis than 5-NBene-2,2-DM in S91 mouse melanoma cells. Furthermore, 2,3-cs/ex-PinD appears to penetrate guinea-pig skin better than 5-NBene-2,2-DM and to induce higher levels of pigmentation. Both 5-NBene-2,2-DM and 2,3-cs/ex-PinD induce synthesis of nitric oxide (NO) in S91 cells, and the melanogenic activity of both compounds is reduced by inhibitors of the NO/cyclic guanosine monophosphate (cGMP)/protein kinase(PK) G signaling pathway, but not by inhibitors of the PKC or PKA pathways. Thus, these bicyclic monoterpene diols appear to induce melanogenesis by the same pathway in S91 cells as that shown previously for ultraviolet radiation in melanocytes (Romero-Graillet et al. (1996) J. Biol. Chem., 271:28052-28056). These compounds also induce NO synthesis, neurite outgrowth, and tyrosine hydroxylase activity in PC12 pheochromocytoma cells. Neurite outgrowth in PC12 cells is blocked by the guanylate cyclase inhibitor, LY83583 (6-anilino-2,8-quinolinequinone), indicating that, similar to S91 cells, the induction of morphological differentiation of PC12 cells by bicyclic monoterpene diols is regulated by a cGMP-dependent pathway.
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PMID:Bicyclic monoterpene diols induce differentiation of S91 melanoma and PC12 pheochromocytoma cells by a cyclic guanosine-monophosphate-dependent pathway. 1019 80

1. In the rat corpus cavernosum (CC), the distribution of immunoreactivity for neuronal and endothelial NO synthase (nNOS and eNOS), and the pattern of NOS-immunoreactive (-IR) nerves in relation to some other nerve populations, were investigated. Cholinergic nerves were specifically immunolabelled with antibodies to the vesicular acetylcholine transporter protein (VAChT). 2. In the smooth muscle septa surrounding the cavernous spaces, and around the central and helicine arteries, the numbers of PGP- and tyrosine hydroxylase (TH)-IR terminals were large, whereas neuropeptide Y (NPY)-, VAChT-, nNOS-, and vasoactive intestinal polypeptide (VIP)-IR terminals were found in few to moderate numbers. 3. Double immunolabelling revealed that VAChT- and nNOS-IR terminals, VAChT- and VIP-IR terminals, nNOS-IR and VIP-IR terminals, and TH- and NPY-IR terminals showed coinciding profiles, and co-existence was verified by confocal laser scanning microscopy. TH immunoreactivity was not found in VAChT-, nNOS-, or VIP-IR nerve fibres or terminals. 4. An isolated strip preparation of the rat CC was developed, and characterized. In this preparation, cumulative addition of NO to noradrenaline (NA)-contracted strips, produced concentration-dependent, rapid, and almost complete relaxations. Electrical field stimulation of endothelin-1-contracted preparations produced frequency-dependent responses: a contractile twitch followed by a fast relaxant response. After cessation of stimulation, there was a slow relaxant phase. Inhibition of NO synthesis, or blockade of guanylate cyclase, abolished the first relaxant phase, whereas the second relaxation was unaffected. 5. The results suggest that in the rat CC, nNOS, VAChT- and VIP-immunoreactivities can be found in the same parasympathetic cholinergic neurons. Inhibitory neurotransmission involves activation of the NO-system, and the release of other, as yet unknown, transmitters.
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PMID:NO synthase in cholinergic nerves and NO-induced relaxation in the rat isolated corpus cavernosum. 1038 33

We have previously reported that atrial natriuretic factor (ANF) increased neuronal norepinephrine (NE) uptake and reduced basal and evoked neuronal NE release. Changes in NE uptake and release are generally associated to modifications in the synthesis and/or turnover of the amine. On this basis, the aim of the present work was to study ANF effects in the rat hypothalamus on the following processes: endogenous content, utilization and turn-over of NE; tyrosine hydroxylase (TH) activity; cAMP and cGMP accumulation and phosphatidylinositol hydrolysis. Results showed that centrally applied ANF (100 ng/microl/min) increased the endogenous content of NE (45%) and diminished NE utilization. Ten nM ANF reduced the turnover of NE (53%). In addition, ANF (10 nM) inhibited basal and evoked (with 25 mM KCl) TH activity (30 and 64%, respectively). Cyclic GMP levels were increased by 10 nM ANF (100%). However, neither cAMP accumulation nor phosphatidylinositol breakdown were affected in the presence of 10 nM ANF. The results further support the role of ANF in the regulation of NE metabolism in the rat hypothalamus. ANF is likely to act as a negative putative neuromodulator inhibiting noradrenergic neurotransmission by signaling through the activation of guanylate cyclase. Thus, ANF may be involved in the regulation of several central as well as peripheral physiological processes such as cardiovascular function, electrolyte and fluid homeostasis, endocrine and neuroendocrine synthesis and secretion, behavior, thirst, appetite and anxiety that are mediated by central noradrenergic activity.
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PMID:Atrial natriuretic factor inhibits norepinephrine biosynthesis and turnover in the rat hypothalamus. 1065 Oct 63

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are present in adrenal chromaffin cells, and are co-secreted with catecholamines suggesting that these natriuretic peptides (NPs) may modulate functions of chromaffin cells in an autocrine and/or paracrine manner. Therefore, we investigated the effects of NPs on tyrosine hydroxylase (TH: a rate-limiting enzyme in biosynthesis of catecholamine) mRNA in rat pheochromocytoma PC12 cells. It was also determined whether the cyclic GMP/cGMP-dependent protein kinase (cGMP/PKG) pathway was involved in theses effects. Finally, we examined the effects of NPs on intracellular catecholamine content to confirm increase of catecholamine synthesis following TH mRNA induction. NPs (0.1 microM) induced significant increases of the TH mRNA (ANP= BNP> CNP). Also, the effects of NPs on TH mRNA were mimicked by 8-bromo cyclic GMP (1mM), and were blocked by KT5823 (1 microM) (inhibitor PKG) or LY83583 (1 microM) (guanylate cyclase inhibitor). Moreover, NPs were shown to induce significant increases of intracellular catecholamine contents (ANP= BNP> CNP). These findings suggest that NPs induced increases of TH mRNA through cGMP/PKG dependent mechanisms, which, in turn, resulted in stimulation of catecholamine synthesis in PC12 cells.
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PMID:Effects of natriuretic peptides (ANP, BNP, CNP) on catecholamine synthesis and TH mRNA levels in PC12 cells. 1083 6

The nitric oxide (NO) donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), induced differentiation of human neuroblastoma NB69 cells to a dopamine phenotype, as shown by phase-contrast microscopy and tyrosine hydroxylase (TH) immunocytochemistry. NB69 cells were treated with 50 to 750 microM SNAP in serum-free-defined medium for 24 h. SNAP treatment did not increase the number of necrotic or apoptotic cells. However, a decrease in the number of viable cells was observed at 750 microM SNAP. In addition, a decrease in (3)H-thymidine uptake was detected at the highest dose of SNAP. An increase in the antiapoptotic Bcl-2 and Bcl-xL protein levels and a decrease in the proapoptotic Bax and Bcl-xS protein levels were also detected by Western blot analysis after SNAP treatment. At low doses (50-125 microM), SNAP induced an increase in catecholamine levels, (3)H-dopamine uptake, TH activity and monoamine metabolism, while a decrease in all these parameters was observed at high doses (250-750 microM). The TH protein content, analyzed by Western blot, remained unchanged in SNAP-treated cells throughout the range of doses studied, when compared with the control group. SNAP produced a dose-dependent decrease in the glutathione (GSH) content of the culture medium, without altering intracellular GSH. In addition, cGMP levels and nitrite concentration, measured in the supernatant of SNAP-treated cells, increased in a dose-dependent manner, as compared to control levels. The guanylate cyclase inhibitor lH-[1,2, 4]oxadiazolo[4,3a]quinoxaline-l-one (ODQ) did not revert the SNAP-induced effect on (3)H-dopamine uptake to control values. These results suggest that NO, released from SNAP, induces differentiation of NB69 cells and regulates TH protein at the post-transcriptional level through a cGMP-independent mechanism.
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PMID:Nitric oxide induces differentiation in the NB69 human catecholamine-rich cell line. 1096 52

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of catecholamines. In a previous report we found that intracerebroventricular administration of nitric oxide (NO) generator sodium nitroprusside (SNP) to conscious male rats inhibited dose-dependently the TH activity of the median eminence (ME). In the present study we have tested the in vitro effects of SNP on TH activity, its possible mediator and action mechanism. Exposure of the ME TH to SNP (50, 100 and 500 microM) caused concentration-dependent inhibition of its enzyme activity. Addition of; reduced hemoglobin Hb (10 microM), a NO scavenger, superoxide dismutase SOD (1000 units/ml), a superoxide scavenger enzyme, or uric acid UA (300 microM), a peroxynitrite scavenger, did not affect the enzyme activity by themselves, but prevented the inhibitory effect of SNP 500 microM. However, the presence of methylene blue MB (100 microM), a guanylyl cyclase inhibitor, did not alter either basal enzyme activity or the inhibitory action of SNP 500 microM. These results suggest that this action of SNP on TH of the ME would be mediated by peroxynitrite generated by the reaction of NO with superoxide.
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PMID:Nitric oxide inhibits tyrosine hydroxylase of rat median eminence. 1107 70

There is evidence suggesting that nitric oxide (NO) may play an important role in dopamine (DA) cell death. Thus, the aim of this study was to investigate the effects of NO on apoptosis and functionality of DA neurones and glial cells. The experiments were carried out in neuronal-enriched midbrain cultures treated with the NO donor diethylamine-nitric oxide complexed sodium (DEA-NO). DEA-NO, at doses of 25 and 50 microM, exerted neurotrophic effects on dopamine cells, increasing the number of tyrosine hydroxylase positive (TH(+)) cells, TH(+) neurite processes, DA levels and [(3)H]DA uptake. A dose of 25 microM DEA-NO protected DA cells from apoptosis. In addition, it induced de novo TH synthesis and increased intracellular reduced glutathione (GSH) levels, indicating a possible neuroprotective role for GSH. However, in doses ranging from 200 to 400 microM, DEA-NO decreased TH(+) cells, DA levels, [(3)H]DA uptake and the number of mature oligodendrocytes (O1(+) cells). No changes in either the amount or morphology of astrocytes and glial progenitors were detected. A dose- and time-dependent increase in apoptotic cells in the DEA-NO-treated culture was also observed, with a concomitant increase in the proapoptotic Bax protein levels and a reduction in the ratio between Bcl-xL and Bcl-xS proteins. In addition, DEA-NO induced a dose- and time-dependent increase in necrotic cells. 1H-[1,2,4]oxadiazolo[4, 3a]quinoxaline-1-one (ODQ, 0.5 microM), a selective guanylate cyclase inhibitor, did not revert the NO-induced effect on [(3)H]DA uptake. Glia-conditioned medium, obtained from fetal midbrain astrocyte cultures, totally protected neuronal-enriched midbrain cultures from NO-induced apoptosis and rescued [(3)H]DA uptake and TH(+) cell number. In conclusion, our results show that low NO concentrations have neurotrophic effects on DA cells via a cGMP-independent mechanism that may implicate up-regulation of GSH. On the other hand, higher levels of NO induce cell death in both dopamine neurones and mature oligodendrocytes that is totally reverted by soluble factors released from glia.
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PMID:Neurotrophic and neurotoxic effects of nitric oxide on fetal midbrain cultures. 1114 78

The effects of the nitric oxide (NO) donor, sodium nitroprusside, on L-DOPA and dopamine release from striatal tissue were evaluated using a static incubation system in which the striatal tissue released between three and six times more L-DOPA than DA, although the DA content was four times higher than that of L-DOPA. Sodium nitroprusside stimulated L-DOPA release in a time- and concentration-dependent (25, 50 and 100 microM) manner. This effect was not due to an increase in L-DOPA synthesis because sodium nitroprusside did not modify the tyrosine hydroxylase activity of striatal tissue. DA release was also stimulated by sodium nitroprusside but it required a higher concentration (500 microM) and longer incubation (60 min). Neither basal nor sodium nitroprusside-stimulated L-DOPA release was influenced by Ca(2+) deprivation (EGTA 5 mM) and/or the presence of nitrendipine (1 microM), a blocker Ca(2+) channel, in the incubation medium. However, cGMP (1 mM) increased L-DOPA release, and the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ) (5 microM), partially blunted the stimulatory effect of sodium nitroprusside 100 microM. In addition, the presence of certain scavengers of free radicals, such as uric acid (300 microM) or melatonin (300 microM) but not of superoxide dismutase (1000 UI/ml) or salicylic acid (300 microM), completely blocked sodium nitroprusside (100 microM)-induced L-DOPA release. These results show that NO stimulates L-DOPA release from striatal tissue by an apparently Ca(2+)-independent mechanism, mediated by cGMP but also by peroxynitrite.
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PMID:Sodium nitroprusside stimulates L-DOPA release from striatal tissue through nitric oxide and cGMP. 1190 14

The aim of the present study was to gain information about adrenergic-, cholinergic- and non-adrenergic, non-cholinergic (NANC)- transmitter systems/mediators in the rat vagina, and to characterize its smooth muscles functionally. Tissue sections from vagina of Sprague Dawley rats were immunolabelled with antibodies against protein gene product 9.5 (PGP), synaptophysin (Syn), tyrosine hydroxylase (TH), vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Circularly cut vaginal smooth muscle preparations from the distal vagina were studied in organ baths. In the paravaginal tissue, a large number of PGP-, NOS-, TH-, VIP-immunoreactive (IR) and few CGRP-IR nerve trunks were observed, giving off branches to the smooth muscle wall. The smooth muscle wall was supplied by a large number of PGP-, Syn-, VAChT-, NPY-, NOS- and TH- IR nerve terminals, whilst only a moderate to few numbers of CGRP-, VIP- and PACAP-IR terminals were identified. Especially the distal part of the vaginal wall, where the circularly running smooth muscle was thickened into a distinct sphincter structure, was very richly innervated, predominantly by PGP- and NOS-IR terminals. Below and within the basal parts of the epithelium in the distal half of the vagina, a large number of PGP- and few NOS- and PACAP-IR varicose terminals were observed. The vaginal arteries were encircled by plexuses of nerve terminals. A large number of these were PGP-, Syn-, VAChT-, NOS-, TH-, NPY- and VIP-IR, and few were CGRP- and PACAP-IR. In isolated preparations of the distal vagina, electrical field stimulation (EFS) caused frequency-dependent contractions, which were reduced by sildenafil, tetrodotoxin (TTX) and phentolamine. In preparations contracted by norepinephrine (NA), EFS produced frequency-dependent relaxations. Pretreatment with the NOS-inhibitor N(G)-nitro-L-arginine, TTX, or the inhibitor of soluble guanylate cyclase, ODQ, abolished the EFS relaxations. In NE precontracted preparations, cumulative addition of sildenafil caused concentration-dependent relaxation. Carbachol contracted the strips concentration-dependently from baseline. It can be concluded that the distal part of the rat vagina forms a distinct smooth muscle sphincter, which is richly innervated by adrenergic, cholinergic and NANC nerves. The present studies suggest that in the rat the L-arginine/NO-system not only plays an important role in the regulation of vaginal smooth muscle tone, but also affects blood flow, and may have sensory functions.
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PMID:Morphological and functional characterization of a rat vaginal smooth muscle sphincter. 1215 17

Nitric oxide (NO) is recognized as an essential intercellular messenger in central and peripheral nervous systems. In the present study, whether NO exerts effects on catecholamine (CA) biosynthetic enzymes was determined in primary cultured bovine chromaffin cells. The NO generators sodium nitroprusside (SNP) and S-nitroso-N-acetyl-D,L-penicillamine, in a dose-dependent manner, upregulated transcript levels of tyrosine hydroxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase, accompanied by long-term increases in their enzyme activities and the intracellular CA levels. The SNP effect was diminished by co-treatment with LY83583, an inhibitor of soluble guanylate cyclase, or H-8, a cyclic GMP (cGMP)-dependent protein kinase inhibitor. Co-treatment with 8-Br-cGMP did not increase further the expression of these enzyme genes induced by SNP. Taken together, the data suggest that NO leads to long-term upregulation of the CA system via induction of the genes involved and that this is mediated by cGMP-dependent signaling pathway.
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PMID:Upregulation of catecholamine biosynthetic enzymes by nitric oxide. 1264 83


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