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)

Heat-stable enterotoxins activate guanylate cyclase, whereas heat-labile enterotoxins stimulate adenylate cyclase. Both classes of toxins cause secretory diarrhea at least in part by stimulating Cl- secretion in the intestine. The mechanism for regulation of Cl- secretion by guanosine 3',5'-cyclic monophosphate (cGMP) was investigated using cultured T84 intestinal cells as a model for intestinal crypt cells. Escherichia coli heat-stable enterotoxin (ST) markedly stimulated cGMP production in T84 cells. Cl- secretion across T84 cell monolayers cultured on permeable filters was stimulated by E. coli ST, cholera toxin, or 8-BrcAMP, but 8-BrcGMP was ineffective. cGMP analogues that are known to be potent and specific activators of cGMP-dependent protein kinase (cG-kinase) also had little effect on 36Cl- uptake by T84 cells cultured in plastic dishes. E. coli ST, forskolin, cholera toxin, or membrane-permeant cAMP analogues markedly increased 36Cl- uptake into T84 cells. The general protein kinase inhibitor, staurosporine, inhibited the stimulation of Cl- permeability elicited by E. coli ST, vasoactive intestinal peptide (VIP), or 8-BrcAMP. DEAE-Sephacel chromatography revealed a predominant type II isoform of cAMP-dependent protein kinase (cA-kinase) in T84 cells, whereas little or no cytosolic cG-kinase activity was found. Treatment of T84 cells with E. coli ST or VIP resulted in an increase in the cA-kinase activity ratio (-cAMP/+cAMP) if the cytosolic enzyme was assayed at reduced temperature (on ice).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of intestinal Cl- transport by heat-stable enterotoxin: activation of cAMP-dependent protein kinase by cGMP. 132 20

Protein phosphorylation has been recognized as a major mechanism by which cellular functions are controlled by neurotransmitters and hormones. In this review, applications of molecular biological techniques to the analyses of regulatory mechanisms of protein phosphorylation by four major second messengers, cAMP, cGMP, diacylglycerol, and Ca2+, are described. 1) Complementary DNA of the regulatory subunit of the cAMP-dependent protein kinase was cloned and expressed in E. coli. Point mutations were introduced in order to analyze functional domains of the subunit. 2) The soluble isoform of guanylate cyclase was purified, and a cDNA of its 70-KD subunit was cloned. Cyclic GMP binding to purified cGMP-dependent protein kinase was characterized using a rapid filtration assay. 3) Primary structure of the catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A) was determined and the presence of the second isoform of the enzyme was shown by the cDNA cloning technique. 4) The regulatory domain of the protein kinase C was expressed in E. coli. Analysis using site-directed mutagenesis revealed that a "zinc finger"-like structure is responsible for the binding of phorbol esters. In these studies, the molecular biological approach has proven to be useful for clarifying the molecular mechanisms of cellular signal transduction related to second messengers and protein phosphorylation.
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PMID:[Second messengers and protein phosphorylation in cellular signal transduction]. 222 19

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).
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PMID:Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase. 747 3

Heat-stable enterotoxins (STa) produced by pathogenic bacteria induce profound salt and water secretion in the gut, leading to diarrhea. Recently, guanylin, an endogenous peptide with properties similar to STa, was identified. While STa and guanylin bind to the same receptor guanylyl cyclase and raise cell cGMP, the signaling mechanism distal to cGMP remains controversial. Here we show that STa, guanylin and cGMP each activate intestinal Cl- secretion, and that this is abolished by inhibitors of cAMP-dependent protein kinase (PKA), suggesting that PKA is a major mediator of this effect. These agents induce Cl- secretion only in cells expressing the wild-type CFTR, indicating that this molecule is the final common effector of the signaling pathway. The involvement of CFTR suggests a possible cystic fibrosis heterozygote advantage against STa-induced diarrhea.
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PMID:Activation of intestinal CFTR Cl- channel by heat-stable enterotoxin and guanylin via cAMP-dependent protein kinase. 751 Jun 34

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

The mechanism of action of vasoactive intestinal peptide (VIP) was examined in isolated gastric and taenia coli muscle cells and compared with that of nitric oxide (NO), sodium nitroprusside (SNP), and isoproterenol. In gastric muscle cells, VIP stimulated NO production, increased adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) levels, and induced relaxation in a concentration-dependent fashion. The NO synthase inhibitor NG-nitro-L-arginine abolished NO and cGMP production and partly inhibited relaxation. The soluble guanylate cyclase inhibitor LY 83583 abolished cGMP production and partly inhibited relaxation. (R)-p-adenosine 3',5'-cyclic phosphorothioate [(R)-p-cAMPS], a preferential inhibitor of cAMP-dependent protein kinase (cAK), and KT5823, a preferential inhibitor of cGMP-dependent protein kinase (cGK), partly inhibited relaxation separately and abolished relaxation in combination. The pattern implied that VIP induced relaxation by activation of cAK and by NO-mediated stimulation of cGMP and activation of cGK. In taenia coli muscle cells, VIP did not increase NO production or cGMP levels: relaxation was accompanied by an increase in cAMP and was partly inhibited by (R)-p-cAMPS and KT5823 and abolished by a combination of both inhibitors. Isoproterenol increased only cAMP levels in both cell types, which induced relaxation by activating cAK at low concentrations of agonist and both cAK and cGK at high concentrations in a pattern identical to that observed with VIP in taenia coli muscle cells. SNP and NO increased only cGMP levels in both cell types, which induced relaxation by activating cGK only. We conclude that cAK and cGK can be activated separately and mediate relaxation independently.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of distinct cAMP- and cGMP-dependent pathways by relaxant agents in isolated gastric muscle cells. 838 96

Smooth muscle cells isolated separately from the caecal circular smooth muscle layer of the guinea pig were used to investigate whether corticotropin releasing hormone (CRH) can inhibit directly the contraction produced by cholecystokinin octapeptide (CCK-8). In addition, the role of adenylate cyclase and guanylate cyclase in the direct inhibitory effect of CRH was examined. CRH inhibited the contractile response produced by 10(-9)M CCK-8 in a concentration-dependent manner, with an IC50 value of 0.16nM. An inhibitor of particulate guanylate cyclase and an inhibitor of soluble guanylate cyclase had no significant effect of the relaxation produced by CRH. In contrast, an inhibitor of adenylate cyclase and an inhibitor of cAMP-dependent protein kinase significantly inhibited the relaxation produced by CRH. This is the first report demonstrating the direct inhibitory action of CRH on the isolated caecal smooth muscle cells via adenylate cyclase system.
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PMID:Direct inhibitory effect of corticotropin releasing hormone on isolated caecal circular smooth muscle cells of guinea pig via adenylate cyclase system. 864 11

C-type natriuretic peptide (CNP), a hormone which stimulates particulate guanylate cyclase activity, was studied for its ability to stimulate chloride permeability through the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells. Two cell lines, Calu-3 and CF-T43, were used as models of normal and cystic fibrosis (CF) airway epithelial cells, respectively. Calu-3 cells, derived from a lung carcinoma, express relatively high levels of wild-type CFTR. CF-T43 is a transformed line derived from a nasal polyp and expresses the mutant CFTR, deltaF508. Calu-3 cells exposed to the nucleotide guanosine-3',5'-monophosphate (cGMP) analogue 8-Br-cGMP exhibit increased 36Cl- efflux, demonstrating that cGMP can mediate changes in chloride permeability. CNP induces a bumetanide-sensitive short circuit current across Calu-3 monolayers. Whole-cell currents stimulated by CNP display linear current-voltage relationships and have inhibitor pharmacology and ion selectivity consistent with CFTR channel activity. Sodium nitroprusside (SNP), an activator of soluble guanylate cyclase, and CNP both increase cGMP levels and short circuit current in Calu-3 cells. In contrast, exposure of CF-T43 cells to CNP resulted in an increased 36Cl- efflux rate only when combined with the adenylate cyclase agonist isoproterenol and the response was sensitive to kinase inhibitors. CF-T43 cells exposed to isoproterenol and SNP showed no increase in chloride efflux. Together, these data indicate that CNP can activate wild-type and mutant CFTR through a cAMP-dependent protein kinase pathway and that the sensitivity of Calu-3 cells for this stimulation is greater than that of the CF-T43 cells.
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PMID:C-type natriuretic peptide increases chloride permeability in normal and cystic fibrosis airway cells. 911 58

The purpose of the present study was to determine whether selective blockade of adenosine 3',5'-cyclic monophosphate (cAMP)- or guanosine 3',5'-cyclic monophosphate (cGMP)-mediated events modulated norepinephrine responses in intestinal microvessels of normal and portal hypertensive rats. Vascular norepinephrine responses were evaluated before and after inhibition of cAMP-dependent protein kinase [protein kinase A(PKA)] with Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) or guanylate cyclase with LY-83583. Male Sprague-Dawley rats were divided into two groups: those with portal hypertension by portal vein stenosis and normal controls. The small intestine was prepared for microcirculatory studies. Arteriolar diameter and erythrocyte velocity were monitored, and microvascular flow was calculated from velocity and diameter data. The preparation was challenged with incremental concentrations of norepinephrine before and after addition of Rp-cAMPS (50 microM) or LY-83583 (30 microM). Arteriolar diameter and blood flow were significantly elevated in portal hypertensive rats; norepinephrine responses were significantly depressed. LY-83583 did not alter arteriolar diameter, blood flow, or norepinephrine responsiveness in normal or portal hypertensive rats. Rp-cAMPS did not affect arteriolar diameter, blood flow, or norepinephrine responsiveness in normal rats. However, in portal hypertensive rats, Rp-cAMPS reduced blood flow by approximately 20% (P < 0.05) and completely restored vascular norepinephrine responses to normal. The results indicate that cAMP- but not cGMP-dependent events are primarily responsible for the loss of microvascular norepinephrine responsiveness in portal hypertensive intestine.
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PMID:Altered vascular norepinephrine responses in portal hypertensive intestine: role of PKA and guanylate cyclase. 914 15

Smooth muscle cells isolated from the caecal circular smooth muscle layers of the guinea pig were used to determine whether adrenomedullin and guanylin can inhibit the contractile response produced by 10(-9) M cholecystokinin octapeptide (CCK-8). In addition, to elucidate each intracellular mechanisms, we examined the effects of an inhibitor of cAMP-dependent protein kinase, an inhibitor of particulate guanylate cyclase, and an inhibitor of soluble guanylate cyclase on the adrenomedullin- or guanylin-induced relaxation of the caecal circular smooth muscle cells. Both adrenomedullin and guanylin inhibited the contractile response produced by CCK-8 in a dose-dependent manner, with IC50 values of 0.12 nM and 2.4 pM, respectively. An inhibitor of cAMP-dependent protein kinase significantly inhibited the relaxation produced by adrenomedullin. In contrast, an inhibitor of particulate guanylate cyclase and an inhibitor of soluble guanylate cyclase did not have any significant effect on the relaxation produced by adrenomedullin. On the other hand, an inhibitor of particulate guanylate cyclase significantly inhibited the guanylin-induced relaxation, although an inhibitor of cAMP-dependent protein kinase and an inhibitor of soluble guanylate cyclase did not have any significant effect on the guanylin-induced relaxation. In this study, we first demonstrated the direct inhibitory effects of adrenomedullin via cAMP system and guanylin via particulate guanylate cyclase system on the isolated caecal circular smooth muscle cells.
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PMID:Direct inhibitory effect of adrenomedullin and guanylin on isolated caecal circular smooth muscle cells of guinea pig. 932 27


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