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)

Atrial natriuretic factor (ANF-R1) receptor is a 130-kDa protein that contains a cytoplasmic guanylate cyclase domain. We report that ATP interacts in an allosteric manner with the ANF-R1 receptor, resulting in reduced ANF binding and enhanced ANF-stimulated guanylate cyclase activity. The modulatory properties of various nucleotides indicate a preference for the adenine family with a rank order of potency of ATP greater than App(NH)p greater than or equal to ADP greater than or equal to AMP while cyclic and guanine nucleotides except GTP are inactive. The negative modulation by ATP of ANF binding is specific for the ANF-R1 receptor subtype since the amount of ANF bound by the guanylate cyclase uncoupled ANF-R2 subtype is increased in the presence of ATP. Furthermore, the effects of ATP on ANF-R1 receptor binding function are still observed with the affinity-purified ANF-R1 receptor, suggesting an allosteric binding site for ATP on the ANF-R1 receptor. In intact membranes, limited proteolysis of the ANF-R1 receptor with trypsin dose-dependently prevents the ATP-induced decrease in ANF binding concomitantly with the formation of a membrane-associated ANF-binding fragment of 70 kDa. These results confirm the direct modulatory role of ATP on hormone binding activity of ANF-R1 receptor and suggest that the nucleotide regulatory binding site is located in the intracellular domain vicinal to the protease-sensitive region.
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PMID:Allosteric modulation by ATP of the bovine adrenal natriuretic factor R1 receptor functions. 165 83

Forty-eight hours after partial (approximately 67%) hepatectomy the activity of the particulate guanylate cyclase was increased by 2-fold in the regenerating rat liver. This increase was not an artifact of membrane isolation procedures, and as determined by 125I-labeled Tyr-28 atrial natriuretic hormone-(1-28) ANF binding, was accompanied by a 2-fold increase in the number of ANF receptors. The Kd of the receptors in membranes of regenerating livers was not significantly different from the Kd of the receptors in livers of sham-operated rats. The linear synthetic descysteine analog of ANF, analog I, which binds only to the 66-kDa receptors, displaced approximately 40% of the specifically bound 125I-ANF in liver membranes from both hepatectomized and sham-operated (control) animals. Affinity cross-linking studies with 125I-ANF confirmed the increase in the 116-kDa ANF receptor in membranes of regenerating livers. In perfused livers derived from control and hepatectomized animals, the basal rates of cGMP production were not significantly different. However, atriopeptin II-stimulated cGMP production was twice as great in regenerating livers as compared with controls. These data demonstrate that the increase in particulate guanylate cyclase activity observed during liver regeneration is due to an increase in the 116-kDa ANF receptor-associated activity. Additionally, our data demonstrate that the regenerating rat liver may be a valuable model with which to study the role of the hepatic ANF receptor/particulate guanylate cyclase.
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PMID:Increase in the number of atrial natriuretic hormone receptors in regenerating rat liver. 167 Jul 70

There has been no direct demonstration of the presence of guanylate cyclase-linked atrial natriuretic factor receptors in renal preglomerular microvasculature. Using [125I]ANF, we have demonstrated the presence of high affinity (Kd = 80 pM) and low affinity (Kd = 7.2 nM) ANF receptors in membranes derived from rabbit renal preglomerular microvessels (afferent arterioles and interlobular arteries). These microvessels also exhibited the presence of particulate bound ANF-sensitive guanylate cyclase. The density of the high affinity ANF receptor in desoxycorticosterone-treated rabbits on a high-salt diet (31 +/- 3 fmol/mg protein) was nearly half of that seen in rabbits on a normal diet (53 +/- 4 fmol/mg protein; p less than 0.01, n = 4). Data from this study demonstrated the presence of renal preglomerular ANF receptors and suggested that these receptors (perhaps in addition to glomerular ANF receptors) may participate in the regulation of extracellular volume.
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PMID:Characterization and physiologic regulation of atrial natriuretic factor receptors in rabbit preglomerular renal microvessels. 167 21

In the present study, we investigated the effects of calmodulin, adenosine 5'-triphosphate (ATP) and pertussis toxin (PT) on phorbol ester (PMA) (a protein kinase C activator) induced inhibition of ANF-stimulated cyclic GMP formation in cells from the human renal cell line, SK-NEP-1. PMA inhibited ANF-stimulated guanylate cyclase activity in particulate membranes by about 65%. Calmodulin reversed this inhibition in a dose dependent manner. ATP potentiated Mg++ but not Mn++ supported guanylate cyclase activity. In PMA treated membranes, ATP potentiating effects were abolished. PMA also inhibited ANF-stimulated cGMP accumulation, but pretreatment with PT prevented this PMA inhibition. PT did not affect basal or ANF-stimulated cGMP accumulation. In conclusion, these results demonstrated that PMA (activated protein kinase C) inhibited ANF stimulation of particulate guanylate cyclase in opposition to the activating effects of calmodulin or ATP in SK-NEP-1 cells. The protein kinase C inhibitory effects appeared to be mediated via a PT-sensitive G protein.
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PMID:The opposing effects of calmodulin, adenosine 5'-triphosphate, and pertussis toxin on phorbol ester induced inhibition of atrial natriuretic factor stimulated guanylate cyclase in SK-NEP-1 cells. 167 90

Natriuretic peptides are structurally related hormones that regulate hemodynamics of the physiological processes of diuresis, water balance, and blood pressure. One of the second messengers of these hormones is cGMP, and the type of receptor that is involved in the generation of cGMP is also a guanylate cyclase. Recent genetic evidence has revealed such a receptor family; two family members, GC-A and GC-B, have been cloned. We now describe the molecular cloning, sequencing, and expression of a cDNA clone from rat adrenal gland that encodes a membrane guanylate cyclase, GC alpha, that, with the exception of two amino acids, is structurally identical to GC-A and conforms to the purported topographical model of GC-A. The two amino acid changes are the substitutions Gln338----His338 and Leu364----Pro364, involving single nucleotide changes, CAG----CAC and CTG----CCG, respectively. Expression studies indicate that GC alpha cyclase activity is independent of the known natriuretic peptides, and direct binding studies demonstrate that GC alpha is not an ANF receptor. To determine the importance of Gln338 and Leu364 in ANF signaling, the GC alpha cDNA regions encoding amino acid residues 338 and 364 were remodeled by oligonucleotide-directed mutagenesis. A double mutant encoding Gln338 and Leu364, and a single-substitution mutant encoding Leu364 expressed both ANF binding and ANF-dependent cyclase activities, but the mutant encoding Gln338 and a deletion mutant lacking residue 364 did not express either of the above activities. These results define the critical role of Leu364 in ANF signal transduction.
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PMID:Site-directed mutational analysis of a membrane guanylate cyclase cDNA reveals the atrial natriuretic factor signaling site. 167 39

The atrial natriuretic factor-R1 (ANF-R1) receptor is known to mediate the biological effects of diverse natriuretic/diuretic/vasorelaxant peptides. In order to investigate the differential selectivity of this class of receptor, we have compared its pharmacological profile for various natriuretic peptides in rat, bovine, and human kidney. In contrast to bovine and rat, human kidney glomeruli do not express significant amounts of ANF-R2 receptor. In addition, the binding of 125I-labeled rat ANF-(99-126) to the ANF-R1 receptor in human and bovine kidney glomeruli is not blocked by rat ANF-(103-123) (pK less than 6), whereas in rat kidney glomeruli this peptide displays high affinity for the ANF-R1 receptor (pK = 8.5). This observation reveals a species heterogeneity between the rat and the human and bovine kidney receptors. In addition, we have observed striking differences in the pharmacological profiles of rat papillary, bovine papillary, and human kidney glomerular receptors, which contain only the 130-kDa ANF-R1 monomer. The bovine and human profiles were similar but diverged from that of the rat. In addition to the species heterogeneity of the ANF-R1 class, we could detect a significant intraspecies heterogeneity. Two distinct profiles could be disclosed, one having high affinity for both ANF and brain natriuretic peptide (BNP) and being identified in all three species studied and the other displaying lower affinity for BNP and being found in rat and human kidneys. We also demonstrate that rat and bovine papillary ANF-R1 receptors are coupled to guanylate cyclase and that ANF and BNP could activate the enzyme with potency similar to their potency in competing for 125I-labeled rat ANF-(99-126) binding. The results presented demonstrate that the ANF-R1 receptor class can be subclassified, based on distinct pharmacological profiles, and indicate a wide diversity within the ANF-R1 receptor family.
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PMID:Pharmacological evidence for the heterogeneity of atrial natriuretic factor-R1 receptor subtype. 168 36

We examined calcium and calmodulin regulation of atrial natriuretic factor stimulation of particulate-membrane guanylate cyclase (ANF-s-GC) in SK-NEP-1 cells. W7 and trifluoropiperazine, but not W5, inhibited whole cellular ANF-stimulated cyclic GMP accumulation (ANF-s-cGMP). EGTA and LaCl3 decreased ANF-s-GC and calmodulin reversed this inhibition. A23187-induced inhibition of ANF-s-cGMP was only partly reversible by IBMX. H7 or staurosporine counteracted the inhibitory effect of A23187. Calcium inhibited basal and ANF-s-GC. These data suggest that at low concentrations of calcium, ANF-s-GC was calcium-calmodulin dependent but high concentrations of calcium inhibited ANF-s-GC through phosphodiesterase, through inhibition of GC, and probably through protein kinase C.
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PMID:Calcium and calmodulin regulate atrial natriuretic factor stimulation of cyclic GMP in a human renal cell line. 168 32

Atrial natriuretic factor (ANF, 10(-7) M) and, even more potently, sodium nitroprusside (SNP, 10(-5)-10(-3) M) stimulated cGMP formation in human peritoneal macrophages. This suggests that the two forms of guanylate cyclase, the particulate form stimulated by ANF and the soluble form activated by SNP, coexist in this cell type. A fall in cAMP levels in parallel with the rise of cGMP levels provoked by ANF and SNP was noticed that was amplified by an increase in the concentration of the phosphodiesterase inhibitor, IBMX. Our finding that ANF, contrary to its action in other tissues, was unable to exert direct inhibitory effects on the adenylate cyclase activity in isolated macrophage membranes, together with the observation that SNP was able to mimic the effect of ANF on cAMP levels indicates that the cAMP-lowering effect of ANF is most likely mediated through the cGMP signal.
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PMID:Atriopeptins and nitroprusside provoke opposite changes in cGMP and cAMP levels in human macrophages. 169 68

Atrial natriuretic factor (ANF, 10(-7) M) and sodium nitroprusside (SNP, 10(-5)-10(-3) M) stimulated cGMP production in human peritoneal macrophages (HPM). This suggests the existence of two separate forms of guanylate cyclase in HPM, e.g. the receptor-related form by ANF and the soluble form by SNP. In parallel with the rise in cGMP levels, both agents provoked a decrease in cAMP levels. Increasing the concentration of the phosphodiesterase inhibitor IBMX (0.2 mM to 1.0 mM) in the incubation media resulted in a significantly greater rise in cGMP levels which was accompanied by a profound decrease in cAMP levels. ANF did not exert any direct or GTP-related effect on cAMP production, which is in contrast to its action in other tissues. These results suggest that cAMP levels can be modulated through a cGMP signal, most likely at the production level. Results also give substantial evidence for the presence of a ANF receptor site on human peritoneal macrophages.
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PMID:Cyclic nucleotides in human macrophages: effects of atrial natriuretic factor and nitroprusside on cGMP and cAMP production. 172 23

ANF can potentially elicit vasorelaxation in vitro which is typically associated with an elevation in tissue levels of cGMP. Hypotension with vasodilation can be observed upon injection of ANF in vivo, however, infusion of the peptide often results in a decreased blood pressure due to a fall in cardiac output, This apparent discrepancy may reflect some of the distinguishing characteristics of ANF-induced vasorelaxation which include activation of particulate guanylate cyclase, a marked regional vascular selectivity, species differences in the relaxation profile and a variable sensitivity depending on the type and degree of contractile preload.
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PMID:Mechanisms of atrial natriuretic factor-induced vasodilation. 196 39


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