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)

Toxic shock syndrome toxin 1 (TSST-1) is a Mr 22,000 protein produced by Staphylococcus aureus. It is thought to be the cause of toxic shock syndrome. We investigated the hypothesis that TSST-1 induces nitric oxide (NO) synthase and that the NO formed may be involved in the pathogenesis of toxic shock syndrome. We used the murine monocyte-macrophage cell line J744.2 that responds to TSST-1 and also expresses NO synthase activity upon immunological stimulation. J774.2 macrophages stimulated with TSST-1 (10-100 nM) generated nitrite, a breakdown product of NO, and induced concentration-dependent elevations of cGMP in the pig kidney epithelial cell line (LLC-PK1). This latter effect was due to the generation of L-arginine-derived NO for it was (i) abolished by oxyhemoglobin (10 microM), a scavenger of NO, or by methylene blue (10 microM), an inhibitor of NO-activated guanylate cyclase; (ii) potentiated by superoxide dismutase (100 units/ml), which prolongs the life of NO; (iii) inhibited by NG-monomethyl-L-arginine (0.3 mM), an inhibitor of NO synthase; (iv) significantly decreased when L-arginine (0.4 mM) in the medium was replaced by D-arginine (0.4 mM). Moreover, TSST-1 (100 nM) enhanced the activity of cytosolic NO synthase in J774.2 cells. Hydrocortisone (1 microM) but not indomethacin (5 micrograms/ml) or salicylic acid (5 micrograms/ml) prevented the generation of NO2- and the increases in cGMP levels in LLC-PK1 cells induced by J774.2 cells stimulated with TSST-1. The effects of hydrocortisone were partially reversed by coincubation with RU 486 (1 microM), an antagonist of glucocorticoid receptors. Thus, TSST-1 and perhaps other exotoxins produced by Gram-positive bacteria induce NO synthase and the increased NO formation may contribute to toxic shock syndrome and possibly to changes in the immune responses that accompany infection.
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PMID:Induction of nitric oxide synthase activity by toxic shock syndrome toxin 1 in a macrophage-monocyte cell line. 137 33

The effect of endothelin (ET) on cyclic GMP levels in cultured porcine kidney epithelial cells, LLC-PK1, was investigated. ET-1 or ET-3, but not big ET-1 or ET C-terminal hexapeptide 16-21, elevated cyclic GMP levels in a concentration-dependent manner with an EC50 value of about 5 x 10(-10) M. This effect of ET-1 was enhanced with superoxide dismutase, diminished with oxyhemoglobin, inhibited with methylene blue, totally dependent on extracellular calcium and unaffected by indomethacin. L-Arginine derivatives, NG-methyl-L-arginine and NG-nitro-L-arginine also inhibited cyclic GMP responses to 10(-8) M ET-1 with IC50 values of 1.2 x 10(-6) M and 7.6 x 10(-8) M, respectively, and the inhibition was prevented with L-arginine. These data strongly suggest that ET-1 stimulates formation of an endothelium-derived relaxing factor-like substance from L-arginine or a related endogenous material(s) in a Ca(++)-dependent fashion, which in turn activates soluble guanylate cyclase to elevate cellular cyclic GMP levels. The concentrations required for these effects were 10 times lower than those required for atrial natriuretic factor. Thus, the effects of ET on cyclic GMP accumulation may be related to the natriuretic effects of ET in vivo.
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PMID:Endothelin increases cyclic GMP levels in LLC-PK1 porcine kidney epithelial cells via formation of an endothelium-derived relaxing factor-like substance. 166 72

Oxytocin, bradykinin, melittin and A23187 increased cyclic GMP levels through activation of soluble guanylate cyclase in cultured porcine kidney epithelial cells, LLC-PK1. NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide formation, decreased both basal and stimulated levels of cyclic GMP in a concentration-dependent manner. L-Arginine, but not D-arginine, augmented basal as well as stimulated levels of cyclic GMP and prevented the inhibition induced by NG-monomethyl-L-arginine. Similar effects of L-arginine were also observed with L-argininamide, L-arginine ethyl ester, L-arginine methyl ester and the dipeptide L-arginyl-L-aspartic acid. NG-monomethyl-L-arginine did not affect cyclic GMP accumulation induced by sodium nitroprusside, an activator of soluble guanylate cyclase, and atrial natriuretic factor, an activator of particulate guanylate cyclase. Stimulatory effects of oxytocin, glyceryl trinitrate, sodium nitroprusside, bradykinin, melittin and A23187 on cyclic GMP accumulation were enhanced with superoxide dismutase and diminished with oxyhemoglobin. However, atrial natriuretic factor-induced cyclic GMP accumulation was not affected. Furthermore, endothelium derived relaxing factor-like activity was detected in the conditioned medium from LLC-PK1 cells stimulated with oxytocin. Based on these data, we conclude that endothelium-derived relaxing factor is produced in this cell type and participates in the regulatory mechanism of cyclic GMP formation as an intra- and intercellular messenger for activation of soluble guanylate cyclase.
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PMID:Formation of endothelium-derived relaxing factor in porcine kidney epithelial LLC-PK1 cells: an intra- and intercellular messenger for activation of soluble guanylate cyclase. 167 Oct 98

Endothelin-1 (ET-1) elevated cyclic GMP levels in cultured porcine kidney epithelial cells (LLC-PK1) in a concentration-dependent manner with an EC50 value of about 5 x 10(-10) M. NG-methyl-L-arginine and NG-nitro-L-arginine inhibited cyclic GMP responses to 10(-8) M ET-1 with IC50 values of 1.2 x 10(-6) and 7.6 x 10(-8) M, respectively, and the inhibition was prevented with L-arginine. ET-1-induced cyclic GMP accumulation was enhanced with superoxide dismutase and diminished with oxyhemoglobin and methylene blue. Furthermore, the effect of ET-1 on the cyclic GMP levels was totally dependent on extracellular Ca2+. ET-3, but not big ET-1 and ET C-terminal hexapeptide16-21, elicited similar cyclic GMP responses as observed with ET-1 at the same concentration range. These data strongly suggest that, in LLC-PK1 cells, ET-1 stimulates formation of an endothelium-derived relaxing factor-like substance from L-arginine in a Ca(2+)-dependent fashion, which in turn activates soluble guanylate cyclase to elevate cellular cyclic GMP levels. The effects of ET on cyclic GMP accumulation in the kidney epithelial cells may be related to the natriuretic effects of ET in vivo.
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PMID:Endothelin-1 stimulates cyclic GMP formation in porcine kidney epithelial cells via activation of the L-arginine-dependent soluble guanylate cyclase pathway. 172 46

Oxytocin increased cyclic GMP levels in LLC-PK1 porcine kidney epithelial cells through activation of soluble guanylate cyclase. NG-Monomethyl-L-arginine and N omega-nitro-L-arginine inhibited oxytocin (10 microM) induced cyclic GMP accumulation with IC50 values of 2.3 microM and 140 nM, respectively, and the inhibition was prevented with L-arginine. Both inhibitors at 100 microM lowered the basal levels of cyclic GMP, but did not affect those induced by 1 microM sodium nitroprusside and 100 nM atrial natriuretic factor. These data support our hypothesis that an endothelium-derived relaxing factor-like substance is formed as the endogenous activator of soluble guanylate cyclase in an L-arginine-dependent fashion in various cell types. N omega-Nitro-L-arginine is 16 times more potent than NG-monomethyl-L-arginine as a specific inhibitor of this pathway in LLC-PK1 cells.
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PMID:N omega-nitro-L-arginine: a potent inhibitor of the L-arginine-dependent soluble guanylate cyclase activation pathway in LLC-PK1 cells. 197 29

Recently, it was shown that in LLC-PK1 kidney epithelial cells hormones such as vasopressin or oxytocin increase cyclic GMP in a receptor-mediated and L-arginine-dependent manner. In the present study, the possible existence of cross-tolerance to vasopressin and oxytocin was investigated in nitrate-tolerant LLC-PK1 cells. Pretreatment with 1 mM glyceryl trinitrate for 3 h decreased cyclic GMP stimulation by 1 microM vasopressin and 1 microM oxytocin by 49% and 54%, respectively. Under the same conditions, cyclic GMP stimulation at 1 microM sodium nitroprusside was diminished by 56% whereas the cyclic GMP response to 100 microM glyceryl trinitrate was virtually abolished. Our results demonstrate that a substantial degree of cross-tolerance to L-arginine-dependent guanylate cyclase activators occurs in nitrate-pretreated nonvascular cells which may be due to glyceryl trinitrate-induced desensitization of soluble guanylate cyclase.
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PMID:Cross-tolerance to L-arginine-dependent guanylate cyclase activators in nitrate-tolerant LLC-PK1 kidney epithelial cells. 197 70

The L-arginine antagonist NG-monomethyl-L-arginine has been shown to inhibit nitric oxide formation from L-arginine in endothelial cells. In the present study NG-monomethyl-L-arginine was used to assess the role of L-arginine for cyclic GMP stimulation by vasopressin in a kidney epithelial cell line (LLC-PK1). Preincubation of cells with 1 mumol/l, 10 mumol/l and 100 mumol/l NG-monomethyl-L-arginine decreased cyclic GMP stimulation at 1 mumol/l vasopressin by 25%, 71% and 90%, respectively. This inhibition by NG-monomethyl-L-arginine was markedly reduced by L-arginine (2 mmol/l) but not D-arginine (2 mmol/l). Cyclic GMP stimulation by the calcium ionophore A23187 was also inhibited by NG-monomethyl-L-arginine and enantioselectively restored by L-arginine. However, NG-monomethyl-L-arginine did not affect cyclic GMP stimulation by sodium nitroprusside that spontaneously releases nitric oxide. These results suggest that, in kidney epithelial cells, vasopressin induces nitric oxide formation from L-arginine leading to activation of soluble guanylate cyclase. It is concluded that nitric oxide formation from L-arginine is not only responsible for endothelium-dependent relaxation but may be a more general pathway with regulatory function for intracellular guanylate cyclase activity.
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PMID:Cyclic GMP stimulation by vasopressin in LLC-PK1 kidney epithelial cells is L-arginine-dependent. 255 24

A line of kidney cells (PK1) which does not possess measurable ANP binding but has an active particulate guanylate cyclase has been identified. The physical characteristics of this enzyme were compared with those of particulate guanylate cyclase and ANP receptors isolated from rat lung. Although receptor and enzyme appear to reside on the same protein in the lung while the cyclase from PK1 cells does not possess ANP binding activity, these proteins exhibit identical physical characteristics. Guanylate cyclase from PK1 cells and rat lung and ANP receptor from lung co-eluted during gel filtration chromatography, with a Stokes radius of 6.1 nm. Also, these activities co-migrated through sucrose density gradients with S20,w values of 10.4 to 10.9. Using these parameters, a molecular weight of about 270 kD was estimated for all three activities. Furthermore, these enzyme activities exhibited similar mobilities in isoelectric focusing gels, with a pI of 6.1. Thus, although particulate guanylate cyclase from lung presumably possesses receptor binding activity, it is physically identical to a form of this enzyme associated with no measurable binding activity. Possible explanations for these observations are discussed.
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PMID:Comparison of particulate guanylate cyclase in cells with and without atrial natriuretic peptide receptor binding activity. 257 8

The effect of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), and oxytocin (OT) on cAMP and cGMP accumulation was investigated in LLC-PK1 kidney epithelial cells. The addition of ANP, AVP, and OT to intact cells produced a time- and concentration-dependent increase in cGMP accumulation. ANP produced a 1.7-fold increase in cGMP at 10 pM and a maximal 28-fold increase in cGMP at 1 microM. ANP had no effect on basal or AVP-induced stimulation of cAMP accumulation. OT was 10-fold more potent than AVP at increasing cGMP levels, producing a 2.1-fold increase in cGMP at 0.1 nM, whereas AVP was 100-fold more potent at increasing cAMP levels. At a concentration of 1 microM, AVP and OT produced a maximal 12 to 14-fold increase in cGMP, while OT and AVP produced 50- and 90-fold increase in cAMP, respectively. The selective OT agonist [Thr4, Gly7]oxytocin was very effective at increasing cGMP, but not at increasing cAMP levels. The V2-vasopressin agonist [deamino-Pen1,Val4, D-Arg8]vasopressin did not increase cGMP levels, but produced a 20-fold increase in cAMP levels. The addition of ANP together with either AVP or OT produced an additive increase in cGMP content. Simultaneous addition of AVP and OT did not lead to a greater increase in cAMP or cGMP levels. These results suggest that the AVP- and OT-induced increase in cGMP is mediated by OT receptors, whereas the increase in cAMP is probably mediated by vasopressin receptors. ANP increased the activity of particulate guanylate cyclase by 6-fold, while AVP and OT has no effect on particulate guanylate cyclase activity. The relatively selective inhibitor of soluble guanylate cyclase, methylene blue, had no effect on the ANP-induced increase in cGMP content in intact cells, but produced a 50% inhibition of the increase in cGMP by AVP and OT. Methylene blue did not alter the stimulation of cAMP by AVP or OT. These results demonstrate that ANP, AVP, and OT increase cGMP in LLC-PK1 kidney epithelial cells. The increase in cGMP by ANP is mediated by particulate guanylate cyclase, whereas AVP and OT probably increase cGMP by interacting with OT receptors coupled to soluble guanylate cyclase.
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PMID:Atrial natriuretic peptide, oxytocin, and vasopressin increase guanosine 3',5'-monophosphate in LLC-PK1 kidney epithelial cells. 289 98

LLC-PK1 epithelial cells and RFL-6 fibroblasts secreted both cyclic AMP (cAMP) and cyclic GMP (cGMP) when costimulated with forskolin and 3-morpholinosydnonimine (a chemical nitric oxide generator). Intracellular cAMP levels as high as 1100 and 12,000 pmol/10(6) cells were achieved for the two cell types, respectively. These levels were high enough to reach approximately 50% saturation of the cAMP transporter and inhibited transport of cGMP to an equal extent, suggesting that the two cyclic nucleotides compete for a common transport system. The rates of secretion of cGMP and cAMP from LLC-PK1 cells increased in proportion to their rates of synthesis as concentrations of stimulant were varied, but increased only 25% relative to intracellular concentrations in response to inhibition of phosphodiesterases by 3-isobutylmethylxanthine. It is proposed that secretion of cyclic nucleotides is not simply proportional to the total intracellular pool in these cells, but rather is coupled to synthesis. In support of this model, oxyhemoglobin was used to trap nitric oxide and block activity of guanylate cyclase in cells treated with 3-morpholinosydnonimine. As a result, secretion of cGMP ceased within 1 min, whereas intracellular levels decreased slowly over 60 min. Probenecid [p-(dipropylsulfamoyl)benzoic acid] is a nonselective antagonist of anion transport that inhibited secretion of cAMP in both cell types but, unexpectedly, blocked synthesis of cGMP, and this was reflected in direct inhibition of soluble guanylate cyclase in cell lysates. Two heat-stable, high molecular weight factors that confer sensitivity to probenecid were identified, and these factors increased the sensitivity of guanylate cyclase to nitric acid by an order of magnitude.
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PMID:Secretion of cyclic GMP by cultured epithelial and fibroblast cell lines in response to nitric oxide. 753 42


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