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)

The heat-stable enterotoxin (STa) of Escherichia coli causes intestinal secretion by stimulating guanylate cyclase, an enzyme believed to be distinct from the STa receptor. Pertussis toxin (PT) has been reported to block the ability of STa to stimulate guanylate cyclase in rat intestinal mucosa (S. A. Epstein, R. A. Giannella, and H. J. Brandwein, FEBS Lett. 203:44-48, 1986). This suggested that a guanine nucleotide regulatory protein (G protein) coupled the STa receptor to guanylate cyclase, a function not previously recognized for G proteins. We sought to explore this phenomenon and, if possible, to identify this G protein. Initial experiments with the human colon carcinoma cell line T84 revealed that higher-than-expected concentrations (1 micrograms/ml) of PT were needed to intoxicate cells, as assessed by ADP-ribosylation of endogenous PT substrate, but that 99 to 100% intoxication could be achieved. Homogenates made from fully intoxicated cells did not differ from controls in basal or STa-stimulated guanylate cyclase activity, and cyclic GMP accumulation in intact T84 cells was not changed by PT treatment. We conclude that a PT-sensitive G protein is not involved in the stimulation of cyclic GMP production by the enterotoxin STa.
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PMID:Failure of pertussis toxin to inhibit activation of guanylate cyclase by the heat-stable enterotoxin of Escherichia coli (STa) in the T84 cell line. 256 75

The natriuretic effects of atrial peptide hormones have been attributed, at least in part, to their stimulation of guanylate cyclase activity in renal cell membranes. The effects of atrial natriuretic factor (ANF) on stimulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation were investigated in cloned human kidney tumor (hKT) cells and parent cells from a human renal tumor epithelial cell line (SK-NEP-1). Human ANF-(99-126) (10(-6)M) stimulated (p less than 0.001) cellular cGMP accumulation in a dose-dependent manner from a basal level of 0.26 +/- 0.04 to 3.73 +/- 0.81 pmol/mg protein/5 mi (mean +/- SEM, n = 13). ANF stimulation of cGMP accumulation was specific, in that high concentrations (10(-6)M) of atriopeptin I [rat ANF-(103-123)], angiotensin II, arginine vasopressin, and amiloride (10(-4)M) did not increase basal cGMP. Amiloride (10(-4)M) enhanced (p less than 0.01, n = 6) the ANF stimulation of cGMP accumulation (1.24 +/- 0.39 pmol/mg protein/5 min), particularly at low doses of ANF (10(-10)M) where stimulation by ANF without amiloride (0.34 +/- 0.08 pmol/mg protein/5 min) was barely distinguishable from a basal level (0.19 +/- 0.02 pmol/mg protein/5 min) of cGMP accumulation. The stimulatory effect of ANF (1.59 +/- 0.07 pmol/mg protein/5 min) was attenuated (0.75 +/- 0.06 pmol/mg protein/5 min, p less than 0.01, n = 6) by preincubation of the cells with pertussis toxin but not by cholera toxin. ANF (4.56 +/- 0.93 pmol/mg protein/5 min, n = 8) did not affect cAMP accumulation (4.32 +/- 0.98 pmol/mg protein/5 min) in hKT cells. This is the first report of an ANF responsive human renal cell line, and its use should facilitate investigation of ANF-receptor interactions.
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PMID:Atrial natriuretic factor effects on cyclic nucleotides in a human renal cell line. 256 5

The heat-stable enterotoxin (STa) of E. coli activates intestinal guanylate cyclase and leads to increased cGMP levels by an as yet undetermined mechanism. In comparing this cGMP system to other known toxin-mediated alterations in cAMP metabolism, we observed that pertussis toxin caused lower levels of intestinal cGMP synthesis in response to purified STa. Another participant in ADP-ribosylation reactions, NAD, enhanced the ability of STa to activate guanylate cyclase, yet had no effect on basal enzyme activity. Niacinamide and isoniacinamide also had no effect on basal activity, but attenuated the STa activation. These results are discussed in relation to current models of hormone/toxin-sensitive adenylate cyclase, and may suggest an involvement of guanine-nucleotide-binding proteins in intestinal cGMP metabolism.
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PMID:Activation of guanylate cyclase by E. coli heat-stable enterotoxin (STa). Modulation by NAD and pertussis toxin. 287 59

Recently we have shown that atrial natriuretic peptide (ANP) inhibits renin release from isolated rat renal juxtaglomerular (JG) cells. ANP in general is thought to act on its target cells by the binding to specific membrane receptors. It is the objective of this contribution to summarize our present knowledge about the sequence of events by which the occupancy of ANP receptors could lead to an inhibition of renin release from juxtaglomerular (JG) cells. It was found that ANP did not affect the intracellular concentration of calcium. ANP led to a dose dependent increase in the intracellular concentration of cyclic GMP and to a dose dependent decrease of cAMPi. Inhibition of renin release from the JG-cells by ANP was clearly correlated to the level of cGMPi and not to the level of cAMPi. Concerning the mechanism by which ANP causes a rise in cGMPi in JG-cells it was found that the effect of ANP on cGMPi was potentiated by the cGMP phosphodiesterase specific inhibitor M & B 22,948. This finding suggests that ANP enhances cGMPi by the stimulation of a guanylate cyclase rather than by the inhibition of a cGMP phosphodiesterase. Moreover, evidence was obtained that the effect of ANP on cGMP, was markedly attenuated after pretreatment of the JG-cells with pertussis toxin. Since pertussis toxin is considered to inactivate guanine nucleotide binding proteins (G-proteins), this result could indicate that ANP receptors are coupled to a guanylate cyclase via a G-protein. Experimental evidence suggests that the G-protein in question might be the inhibitory unit (Ni) of the adenylate cyclase.
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PMID:Transmembrane signalling of atrial natriuretic peptide in rat renal juxtaglomerular cells. 287 65

The cellular cGMP content increased in response to a variety of receptor agonists, which activate [e.g., prostaglandin (PG) E1, E2, and F2 alpha] or inhibit (e.g., alpha-adrenergic, muscarinic, and opiate agonists) adenylate cyclase in neuroblastoma X glioma hybrid NG108-15 cells. The responses were additive when PGF2 alpha and enkephalin were mixed. The inhibitory guanine nucleotide regulatory protein (Ni) is involved in adenylate cyclase inhibition; this function of Ni is lost when it is ADP-ribosylated by islet-activating protein (IAP), pertussis toxin [H. Kurose, T. Katada, T. Amano, and M. Ui (1983) J. Biol. Chem. 258, 4870-4875]. The cGMP rise induced by stimulation of the receptors linked to adenylate cyclase inhibition was also diminished by IAP; the time course and dose response for the IAP-induced diminution were the same between adenylate cyclase inhibition and cGMP generation. Ni thus appears to mediate guanylate cyclase activation as well as adenylate cyclase inhibition initiated via the same receptors. Melittin also increased cGMP. No additivity was shown when enkephalin and melittin were combined, suggesting that phospholipase A2 might play a role in Ni-mediated guanylate cyclase activation. On the other hand, the PGF2 alpha-induced cGMP rise was associated with increased incorporation of 32Pi into phosphatidylinositol; was not affected by cholera toxin, IAP or forskolin; and showed no additivity when combined with A23187, which increased cGMP by itself. PGs would occupy receptors linked to phosphatidylinositol breakdown, thereby increasing the availability of intracellular Ca2+, which is responsible for guanylate cyclase activation. Thus, dual pathways are proposed for a receptor-mediated cGMP rise in NG108-15 cells.
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PMID:Dual pathways of receptor-mediated cyclic GMP generation in NG108-15 cells as differentiated by susceptibility to islet-activating protein, pertussis toxin. 298 51

As noted previously, in N1E-115 neuroblastoma cells, carbamylcholine, a muscarinic cholinergic agonist, increased cGMP over 15-fold and decreased basal and prostaglandin E1 (PGE1)-stimulated cAMP content. In contrast to the stimulatory effects of PGE1 on cAMP, which were immediate, the carbamylcholine-induced decrease in basal and PGE1-stimulated cAMP exhibited a delay. The delay in carbamylcholine inhibition was independent of the extent of adenylate cyclase activation. Although basal cAMP content was suppressed within 30 sec after addition of carbamylcholine, inhibition was not maximal for at least 2 min following agonist addition; the delay was similar in cells exposed to PGE1 for 10 min prior to carbamylcholine but could be eliminated by incubation of the cells with muscarinic cholinergic agonist for 5 min prior to addition of prostaglandin. N1E-115 neuroblastoma cells possess a 41,000-Da membrane protein believed to be a component of the inhibitory GTP-binding protein of adenylate cyclase that is ADP ribosylated by pertussis toxin. Incubation of the cells with pertussis toxin prior to the addition of carbamylcholine reduced the maximal extent of inhibition of cAMP content and prevented the [32P]ADP-ribosylation of a 41,000-Da protein by toxin and [32P]NAD in membrane preparations from these cells. Incubation of cells with pertussis toxin, however, did not significantly alter the dose-response curve for carbamylcholine effects on cGMP. Even high concentrations of carbamylcholine, effective in stimulating cGMP, had minimal effects on cAMP content in toxin-treated cells; thus, ADP-ribosylation of Gi converts the adenylate cyclase but not the guanylate cyclase system to an agonist-insensitive state.
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PMID:Effects of pertussis toxin on cAMP and cGMP responses to carbamylcholine in N1E-115 neuroblastoma cells. 299 40

We studied the role of cyclic guanosine monophosphate (cGMP) as a mediator of the reduction of L-type calcium current (ICa) induced by muscarinic receptor stimulation and by nitric oxide in isolated guinea-pig ventricular cells using the whole-cell patch-clamp technique. Our results show that when the level of cyclic adenosine monophosphate was increased by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), stimulation of a pertussis-toxin (PTX)-sensitive muscarinic receptor by carbachol (1 microM) reduced the calcium current increase from 80.6 +/- 23.5% to 19.8 +/- 9.6% over the control and this effect was prevented by methylene blue (10 microM), an inhibitor of the soluble guanylate cyclase. Pipette solution containing 10 microM cGMP reduced the enhancement of ICa by IBMX from 121.9 +/- 11.6% to 14.2 +/- 5.4% above the control. Sodium nitroprusside (10 microM), a spontaneous donor of nitric oxide, and consequently a stimulator of soluble guanylate cyclase, also reduced IBMX-stimulated ICa from 115.2 +/- 13.2% to 32.2 +/- 6.9% above control and the sodium nitroprusside effect was also suppressed by methylene blue. The latter two reagents were ineffective on basal ICa.
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PMID:Guanylate-cyclase-mediated inhibition of cardiac ICa by carbachol and sodium nitroprusside. 751 32

The present experiments were devoted to analyzing the hypothesis that somatostatin (SS) could modulate glomerular filtration rate by interacting with mesangial cells. Studies were performed in cultured human mesangial cells, passages 3-5. Radioligand experiments demonstrated the presence in the cells of two kinds of receptors, with high (dissociation constant 14 pM. Number of sites: 426 fmol/mg) and low (dissociation constant 56 pM. Number of sites: 20, 111 fmol/mg) affinity. SS prevented in a dose-dependent manner the reduction in planar cell surface area induced by 100 nM Angiotensin II (AII). This effect was not inhibited by the blockade of the vasorelaxing prostaglandins (indomethacin, 10 microM), nitric oxide (L-N-methyl-arginine, 0.2 mM), adenylate cyclase (2,5'-dideoxyadenosine, 0.1 mM), or guanylate cyclase (Methylene blue, 30 microM; LY-83583, 10 microM), but it was potentiated by zaprinast, an inhibitor of the cyclic GMP (cGMP)-specific phosphodiesterase. SS also blocked the increase in myosin light chain phosphorylation induced by AII. SS increased cGMP synthesis by cultured human mesangial cells, an effect that seemed to be dependent on the stimulation of a particulate guanylate cyclase. Preincubation of the cells with pertussis toxin (0.5 microgram/ml) inhibited the effect of SS on the AII-dependent changes in planar cell surface area, as well as the SS-dependent cGMP stimulation. In summary, these results demonstrate the ability of SS to relax cultured human mesangial cells, thus supporting a role for this peptide in the regulation of the glomerular filtration rate. The SS-dependent mesangial cell relaxation may be due to changes in the intracellular concentrations of cGMP, as a consequence of the activation of a particulate guanylate cyclase.
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PMID:Effects of somatostatin on cultured human mesangial cells. 762 80

Prostaglandin E2 (PGE2) has a cytoprotective role in the gastric parietal cell. PGE2 opened a housekeeping basolateral Cl- channel of rabbit gastric parietal cells, the single channel conductance of which was about 0.3 picosiemens. In the present patch-clamp and Fura 2 fluorescence studies, we found that PGE2 increased the intracellular free Ca2+ concentration ([Ca2+]i) and that PGE2-induced opening of the Cl- channel depended on the increase of [Ca2+]i. A novel bifunctional prostaglandin EP3 agonist/EP1 antagonist, 5(Z)-7-[1S, 2S, 3S, 5R)-3-(trans-beta-styren) sulfonamido-6,6-dimethylbicyclo- (3.1.1)hept-2-yl]-5-heptenoic acid, also increased both [Ca2+]i and channel opening. The PGE2-induced effect was mediated via production of nitric oxide (NO); that is, NG-monomethyl-L-arginine, an inhibitor of NO production, markedly inhibited the PGE2-induced channel opening, and nitroprusside, a NO donor, induced the channel opening in the absence of PGE2. Both PGE2 and A23187, Ca2+ ionophore, elevated the cGMP content of isolated parietal cells. The A23187-induced channel opening was abolished by methylene blue, a guanylate cyclase inhibitor. In conclusion, we found that the PGE2-induced opening of the housekeeping Cl- channel in the parietal cell involves the EP3 receptor-mediated increase in [Ca2+]i via a pertussis toxin-sensitive GTP-binding protein, resulting in successive production of NO and cGMP.
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PMID:A gastric housekeeping Cl- channel activated via prostaglandin EP3 receptor-mediated Ca2+/nitric oxide/cGMP pathway. 764 28

A recently discovered endogenous autacoid, C-type natriuretic peptide, was tested in a pheochromocytoma (PC12) cell line for effects on 1) catecholamine release induced by a depolarizing stimulus, 2) guanylyl and adenylyl cyclase activities, and 3) specific 125I-labeled atrial natriuretic peptide (ANP) binding. C-type natriuretic peptide suppressed evoked neurotransmitter release in the absence of guanylyl cyclase activation or adenylyl cyclase inhibition; however, both a "clearance" (ANP-C) receptor binding agent, des-[Gln18Ser19Gly20Leu21Gly22]-ANF-(4-23)-NH2 (cANF), and pertussis toxin prevented this neuromodulatory effect. The C-type natriuretic peptide preferentially bound to receptors that also bound cANF. The results suggest that C-type natriuretic peptide suppressed evoked neurotransmitter efflux by binding to ANP-C receptors coupled to a pertussis toxin-sensitive process; furthermore, the neuromodulatory effect of C-type natriuretic peptide occurred independently of guanylyl cyclase activation or adenylyl cyclase inhibition. The novel aspects of these findings are 1) neuromodulatory effects of C-type natriuretic peptide, 2) guanylyl cyclase-independent actions of C-type natriuretic peptide, and 3) ANP-C receptors mediating C-type natriuretic peptide actions.
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PMID:C-type natriuretic peptide neuromodulates via "clearance" receptors. 773 46


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