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)

1. The mechanism of human sunburn is poorly understood but its characteristic features include the development of erythema. In this study we attempted to determine whether human keratinocytes possess a nitric oxide (NO) synthase (NOS), if this enzyme could be activated to release NO following exposure to ultraviolet B (u.v.B) and to define whether this photo-induced response could be involved in the pathogenesis of sunburn erythema. 2. Treatment of human keratinocytes with various doses of u.v.B (290-320 nm) radiation (up to 100 mJ cm-2) resulted in a dose-dependent release of NO and cyclic GMP production that was reduced by NG-monomethyl-L-arginine (L-NMMA). 3. u.v.B irradiation of keratinocyte cytosol at varying doses (up to 50 mJ cm-2), resulted in a gradual rise in NO production, with a concomitant increase in soluble guanylate cyclase activity (sGC). 4. NOS isolated from the keratinocyte cytosol was constitutively expressed and was dependent on NADPH, Ca2+/calmodulin, tetrahydrobiopterin and flavins. 5. In reconstitution experiments, when purified NOS was added to purified sGC, both isolated from keratinocyte cytosol, a four fold increase in cyclic GMP was observed. The GMP was increased by NO synthesized following u.v.B radiation (up to 20 mJ cm-2) of NOS. 6. In in vivo experiments, guinea-pigs were subjected to u.v.B light. A Protection Factor (PF) of 8.71 +/- 2.85 was calculated when an emulsified cream formulation containing L-NMMA (2%) was applied to their skin. 7. The present results indicate that u.v.B radiation acts as a potent stimulator of NOS in keratinocytes. NO is lipophilic and may diffuse out of the keratinocytes, activating sGC in endothelial cells and neighbouring smooth muscle cells. This may be a major part of the integrated response of the skin leading to vasodilatation and erythema.
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PMID:Release by ultraviolet B (u.v.B) radiation of nitric oxide (NO) from human keratinocytes: a potential role for nitric oxide in erythema production. 762 Jul 17

Photobleaching of rhodopsin in rod photoreceptors activates the visual cascade system leading to a decrease in cyclic GMP and the closure of cGMP-gated channels in the rod outer segment plasma membrane. Calcium plays an important role in the recovery of the rod outer segment to its dark state by regulating the resynthesis of cGMP by guanylate cyclase. Here we report that calmodulin, a Ca(2+)-binding protein present in the rod outer segment, increases the apparent Michaelis constant of the channel for cGMP. This results in a decrease in the rate of cation influx into the rod outer segment by two- to sixfold at low cGMP concentrations and has the effect of increasing the sensitivity of the channel to small changes in cGMP levels during phototransduction. Biochemical studies indicate that calcium-calmodulin binds to a protein of M(r) 240K which is tightly associated with the channel. On the basis of these studies, Ca2+ is suggested to play a central role in photorecovery and light adaptation, not only by regulating guanylate cyclase, possibly through recoverin, but also by modulating the cGMP-gated channel through calmodulin interaction with the 240K protein.
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PMID:Modulation of the cGMP-gated channel of rod photoreceptor cells by calmodulin. 767 44

The synaptosomes from canine ileal deep muscular plexus possess a nitric oxide (NO)-sensitive soluble guanylate cyclase, as demonstrated by approximately 3- to 4-fold elevation of synaptosomal cyclic GMP levels in the presence of either 1 mM sodium nitroprusside or L-arginine (20-1,000 microM) plus 1 mM NADPH. The activating effect of L-arginine on synaptosomal soluble guanylate cyclase was related to its enzymatic conversion to citrulline by NO synthase. The synaptosomal NO synthase was found to exhibit both calcium-independent and calcium/calmodulin-dependent components accounting for approximately 2- to 2.5-fold and 7- to 8-fold increases in the basal activity, respectively. The absolute magnitude of these activities was several-fold greater compared to the activities observed in the isolated cells of circular smooth muscle. The synaptosomal Ca-independent and Ca/calmodulin-dependent NO synthase activities were inhibited by methylene blue and L-NG-arginine methyl ester. The NO synthase activity was also attenuated in the presence of cyclic AMP (10 microM). Such an inhibition was related primarily to the suppression of Ca-independent activity. The ability of enteric nerves to generate NO from L-arginine strongly suggests the involvement of this process in the biochemical mechanisms underlying the neurogenic control of intestinal motility.
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PMID:Nitric oxide synthase in the autonomic nervous system of canine ileum. 767 46

We show here that the human cervix carcinoma cell line ME-180 expresses a constitutive nitric oxide (NO) synthase, as demonstrated by formation of [3H]citrulline and nitrite. The enzyme is dependent on tetrahydrobiopterin, NADPH, flavins and Ca2+/calmodulin. Enzyme activity is located in the cytosol rather than in the membrane fraction and can be inhibited by NG-monomethyl-L-arginine (NMMA). An antiserum to NO synthase purified from porcine cerebellum inhibited the enzyme activity. ME-180 cells released NO, as was shown by stimulation of guanylate cyclase (EC 4.6.1.2) in RFL-6 detector cells; this release was stimulated 8-fold by the Ca2+ ionophore A23187 and 2-fold by increasing the intracellular tetrahydrobiopterin levels with cytokines. This is the first characterization of a Ca2+/calmodulin-dependent NO synthase activity in human epithelial-type tumour cells.
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PMID:Ca2+/calmodulin-dependent nitric oxide synthase activity in the human cervix carcinoma cell line ME-180. 767 33

In addition to mediating several physiological functions, nitric oxide (NO) has been implicated in the cytotoxicities observed following activation of macrophages or excess stimulation of neurons by glutamate. We extend our previous observations of glutamate-stimulated, NO-mediated neurotoxicity in primary cultures of rat fetal cortical, striatal, and hippocampal neurons. Neurotoxicity elicited by either NMDA or sodium nitroprusside (SNP) exhibits a similar concentration-effect relationship and time course. The concentration-effect curve of NMDA-induced neurotoxicity is shifted to the right in the presence of nitro-L-arginine and farther to the right in arginine-free media. The rank order of potency of several NO synthase (NOS) inhibitors in preventing neurotoxicity is the same as the rank order of these compounds in inhibiting NOS, and this inhibition is stereospecific. NMDA neurotoxicity is also prevented by flavoprotein inhibitors and calmodulin inhibitors, fitting with the roles of flavoproteins and calmodulin as NOS regulators. 8-Bromo-cGMP and guanylyl cyclase inhibitors do not affect neurotoxicity, while superoxide dismutase attenuates neurotoxicity. NOS neurons appear to be the source of neurotoxic NO in culture, as lesions of these neurons with 20 microM quisqualate diminish subsequent NMDA neurotoxicity. Moreover, NMDA neurotoxicity develops over time in culture coincident with the expression of NOS. Immunohistochemical localization of NOS in cultures and intact brain demonstrates widespread distribution of the cell processes suggesting that NOS neurons contact the majority of cortical neurons and so could mediate widespread neurotoxicity.
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PMID:Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. 768 76

Nitric oxide (NO) is synthesized in mammalian neurons by Ca2+/calmodulin activated NO synthase and functions as a signalling molecule by activating soluble guanylyl cyclases in target cells. We demonstrate here that both NO synthase and NO-activated guanylyl cyclase are present in the brain of the locust Schistocerca gregaria. Our observations indicate, for the first time, that the NO-cyclic GMP signalling pathway exists in invertebrate nervous systems.
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PMID:Nitric oxide synthesis and action in an invertebrate brain. 769 Jun 76

Vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI) receptors and the signaling pathways to which they are coupled were characterized in dispersed gastric smooth muscle cells. Radioligand binding using 125I-labeled VIP and PHI identified 4 classes of receptors: VIP-preferring and PHI-preferring receptors recognized by both ligands and readily desensitized by the preferred ligand, and VIP-specific and PHI-specific receptors recognized by only 1 ligand and resistant to desensitization. All except VIP-specific receptors were coupled to adenylate cyclase. VIP-specific receptors mediated a G protein-coupled Ca2+ influx that led to activation of NO synthase (NOS), NO-dependent activation of soluble guanylate cyclase, and activation of guanosine 3',5'-cyclic monophosphate (cGMP) kinase resulting in muscle relaxation. The entire cascade was blocked by Ca2+ channel and/or calmodulin antagonists. The NOS inhibitor NG-nitro-L-arginine abolished L-[3H]citrulline (coproduct of NO synthesis) and cGMP generation and partly inhibited (52 +/- 4%) relaxation. The components of response mediated by VIP-specific receptors (increase in [Ca2+]i, L-[3H]citrulline, and cGMP) were preserved after desensitization. Insertion of guanosine 5'-O-(beta-thio)diphosphate into reversibly permeabilized muscle cells abolished responses mediated by VIP-preferring and VIP-specific receptors. VIP stimulated both adenosine 3',5'-cyclic monophosphate (cAMP)-kinase and cGMP-kinase activities consistent with stimulation of cAMP and cGMP. Both kinases contributed to relaxation that was partly inhibited by cAMP-kinase [H-89 and (R)-p-adenosine 3',5'-cyclic monophosphorothioate] and cGMP-kinase (KT-5823) inhibitors and abolished by a combination of the 2 types of inhibitors. We conclude that VIP-specific receptors mediate a G protein-coupled Ca2+ influx leading to activation of a constitutive Ca2+/calmodulin-dependent NOS and generation of NO, which is partly responsible for relaxation in smooth muscle.
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PMID:VIP-mediated G protein-coupled Ca2+ influx activates a constitutive NOS in dispersed gastric muscle cells. 769 77

1. SKPYMRFamide, a novel FMRFamide-like endogenous peptide reversibly decreases excitatory responses (depolarization and inward current) evoked by local ionophoretic application of acetylcholine (ACh) onto the soma of identified neurons F1, F2, F4 and F5/6 of the land snail, Helix aspersa. 2. Threshold concentrations of SKPYMRFamide for an inhibitory action on ACh-induced responses are 0.5-1 mumoll-1. This modulatory action of peptide is dose- and time-dependent. 3. It is concluded that SKPYMRFamide inhibits ACh receptors through activation of specific binding sites on the plasma membrane. 4. The possible role of different second messengers in the modulatory influence of SKPYMRFamide on ACh receptors was tested using 13 modulators of different second messenger systems. 5. The results indicate that SKPYMRFamide may inhibit ACh receptors through activation of one or more of the following systems: phospholipases C, A2, NO-synthase, soluble guanylate cyclase and lipoxygenases which elevate basal intracellulal levels of NO, cGMP, arachidonic acid, acyclic eicosanoids, inositol-1,4,5-trisphosphate (I(1,4,5)P3), I(1,4,5)P3-dependent Ca(2+)-mobilization followed by activation of calmodulin and Ca2+/calmodulin-dependent protein kinase II. Protein kinases A, C and cyclic eicosanoids do not appear to participate in modulatory action of SKPYMRFamide.
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PMID:Inhibitory action of SKPYMRFamide on acetylcholine receptors of Helix aspersa neurons: role of second messengers. 778 22

Human placenta synthesizes and secretes large amounts of CRH during the second and third trimesters. In the hypothalamus, nitric oxide (NO) has been reported to affect CRH release. We studied the effect of NO on the regulation of placental CRH secretion. The effect of the NO donor sodium nitroprusside (SNP) on basal and KCl-stimulated CRH release was examined in cultured human syncytiotrophoblasts. CRH secretion and intracellular concentrations of cGMP, calmodulin-dependent protein kinase (CaM-PK), protein kinase-G (PKG), protein kinase-C, and cAMP-dependent protein kinase holoenzyme were measured under basal conditions and after treatment with a depolarizing concentration of KCl and with SNP. The results showed that depolarization (3 h) increased CRH release 4-fold (from basal value of 5.16 +/- 0.65 to 19.31 +/- 4.46 fmol/10(6) cells); SNP (100 mumol/L) decreased both basal (0.42 +/- 0.21 fmol/10(6) cells) and KCl-stimulated CRH release (0.94 +/- 0.32 fmol/10(6) cells). KCl also increased the activity of CaM-PK in the cell membrane and both cytosolic and membrane PKG activity, whereas the activities of protein kinase-C and cAMP-dependent protein kinase holoenzyme were unchanged. SNP increased intracellular cGMP concentrations after 10, 60, and 180 min. Methylene blue (100 mumol/L), a guanylate cyclase inhibitor, blocked the inhibitory effects of SNP on CRH release. These results suggest that NO exerts inhibitory effects on both basal and KCl-stimulated CRH release from placental syncytiotrophoblasts through a cGMP-mediated pathway. In addition, as KCl-induced changes in the cell membrane were blocked by SNP, CaM-PK may be involved in KCl-stimulated CRH release. KCl may also sensitize the inhibitory pathway involved in the regulation of CRH release by increasing cellular PKG levels. The effects of KCl and SNP on CRH release are more complex than simple activation of CaM-PK and PKG activity, as other cellular signal transduction pathways are also modulated.
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PMID:Basal and KCl-stimulated corticotropin-releasing hormone release from human placental syncytiotrophoblasts is inhibited by sodium nitroprusside. 791 33

Mastoparan potently stimulated catalytic activity of guanylate cyclase-coupled atrial natriuretic factor receptor (GC-A/ANF-R), both in the plasma membranes and intact Leydig tumor (MA-10) cells. In plasma membrane preparations, a maximum of 5-fold GC catalytic activity was stimulated by 100 microM mastoparan and the half maximum stimulation (EC50) was achieved at 40 microM concentration. Mastoparan potentiated GC activity by more than 40%, above the level, stimulated by ANF. Mas 7, an active analog of mastoparan, stimulated the GC activity in a similar manner to mastoparan whereas Mas 17, an inactive analog, did not enhance GC activity. In membranes prepared from mastoparan-treated intact MA-10 cells, GC catalytic activity was enhanced by more than 4-fold as compared with untreated control cells. Pretreatment of membranes with either anti-Gs alpha or anti-Gi alpha antibodies had no effect on mastoparan-stimulated GC activity, however, anti-Go alpha antibodies inhibited the stimulatory effect of mastoparan by almost 50%. Agents known to modulate the effect of mastoparan such as EGTA (Ca2+ chelator), W7 (calmodulin inhibitor) and staurosporine (protein kinase C inhibitor) had no effect on the mastoparan-stimulated GC activity. Mastoparan enhanced the ANF-stimulated GC activity in detergent solubilized membrane preparations without a significant change in ANF-binding capacity. The data establish a role for mastoparan in the ANF-dependent stimulation of GC-A/ANF-R catalytic activity, both in the plasma membrane preparations and intact Leydig tumor (MA-10) cells. Furthermore, these findings provide new evidence that mastoparan (isolated from wasp venom) potently stimulates guanylate cyclase activity of GC-A/ANF-R by activating G-proteins.
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PMID:Modulation of guanylate cyclase-coupled atrial natriuretic factor receptor activity by mastoparan and ANF in murine Leydig tumor cells: role of G-proteins. 794 43


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