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)

Bovine photoreceptor guanylate cyclase (ROS-GC) consists of a single transmembrane polypeptide chain with extracellular and intracellular domains. In contrast to non-photoreceptor guanylate cyclases (GCs) which are activated by hormone peptides, ROS-GC is modulated in low Ca2+ by calmodulin-like Ca(2+)-binding proteins termed GCAPs (guanylate cyclase-activating proteins). In this communication we show that, like the native system, ROS-GC expressed in COS cells is activated 4-6-fold by recombinant GCAP1 at 10 nM Ca2+ and that the reconstituted system is inhibited at physiological levels of Ca2+ (1 microM). A mutant ROS-GC in which the extracellular domain was deleted was stimulated by GCAP1 indistinguishable from native ROS-GC indicating that this domain is not involved in Ca2+ modulation. Deletion of the intracellular kinase-like domain diminished the stimulation by GCAP1, indicating that this domain is at least in part involved in Ca2+ modulation. Replacement of the catalytic domain in a non-photoreceptor GC by the catalytic domain of ROS-GC yielded a chimeric GC that was sensitive to ANF/ATP and to a lesser extent to GCAP1. The results establish that GCAP1 acts at an intracellular domain, suggesting a mechanism of photoreceptor GC stimulation fundamentally distinct from hormone peptide stimulation of other cyclase receptors.
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PMID:Calcium modulation of bovine photoreceptor guanylate cyclase. 867 7

The inhibitory effect of atrial natriuretic peptide (ANP) on angiotensin II (AII)-stimulated aldosterone secretion has been previously studied in rat and bovine adrenal zona glomerulosa cells in primary culture. However the understanding of the mode of action of ANP at the molecular level has been hampered by limitations of those primary cell culture systems and by the lack of cell lines from human adrenal cortex. Here we demonstrate the presence of fully functional ANP receptors in the recently characterized AII-responsive adrenocortical carcinoma cell line H295R. Specific saturable binding of 125I-rANP to H295R cell membrane preparations revealed a single class of high affinity binding sites with a density of 20 fmol/mg of protein. The pharmacological profile of this ANP receptor was documented by competitive binding of 125I-rANP with naturally occurring natriuretic peptides. rANP was the most potent with a Kd of 42 pM. pBNP32 was less potent with a Kd of 174 pM. 125I-rANP binding was not competed by pCNP (NPRB-specific ligand) nor by C-ANF (NPRC-specific ligand). Photoaffinity labeling of membrane preparations with 125I-BPA-ANP revealed a single specific protein of molecular weight around 130 kDa. This protein was further identified by immunodetection with a specific antibody directed to the human ANP-specific receptor NPRA. Natriuretic peptides stimulated cGMP production by the receptor-coupled guanylate cyclase with the same specificity. Aldosterone production by AII-stimulated H295R cells was dose-dependently inhibited by rANP with an ED50 of 1.5 nM. In addition, we used this model to test two chimeric analogs of ANP and BNP. pBNP1 and pBNP3 were, respectively, 4- and 2-fold more potent than rANP in competing for 125I-rANP binding with Kd of 10 and 20 pM. pBNP1 was 24-fold more potent in inhibiting AII-stimulated aldosterone production with ED50 of 63 pM. pBNP1 is therefore the most potent natriuretic peptide analog tested. In summary, the human H295R cell line contains NPRA receptors positively coupled to the particulate guanylate cyclase and that antagonize angiotensin II stimulation of aldosterone secretion.
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PMID:The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. 873 99

These studies were designed to characterize the atrial natriuretic peptide (ANF) receptor subtypes [guanylyl cyclase natriuretic peptide receptors (NPR-A, NPR-B) and NPR-C] in lungs of normal hamsters and to evaluate alterations in receptor kinetics in genetic cardiomyopathy (CMO), a model of human congestive heart failure. Lung membranes were obtained from normal and CMO 200-to 230-day-old hamsters. Cross-linking and competitive binding receptor assays using 125I-labeled human ANF showed that lung membranes exhibit NPR, mainly guanylyl cyclase NPR-A and clearance NPR-C receptors. Stimulation of guanylyl cyclase by ANF and C-type natriuretic peptide (CNP) confirmed the presence of NPR-A and NPR-B. The maximum binding capacity of total ANF binding sites (442 +/- 68 vs. 271 +/- 57 fmol/mg protein, P < 0.05) was reduced, but dissociation constant (0.26 +/- 0.04 vs. 0.41 +/- 0.08 nM) was not altered in CMO animals. Similar reductions were observed in the binding sites for brain natriuretic peptide (BNP; 438 +/- 83 vs. 236 +/- 53 fmol/mg protein) and CNP (321 +/- 80 vs. 165 +/- 56 fmol/mg protein, P < 0.05) which may reflect a decline in NPR-A and NPR-B and/or NPR-C. Acid wash improved binding of 125I-labeled rat ANF to lung membranes of both normal and CMO hamsters, but the tendency towards reduced binding in CMO hamsters did not reach statistical significance, implying that downregulation may not have been due only to prior occupancy of the receptors. Transcripts of NPR-A, NPR-B, and NPR-C receptors in hamster lungs were detected by quantitative polymerase chain reaction. Compared with normal controls, the CMO hamster lung NPR-A mRNA was reduced by 50%, but NPR-B mRNA and NPR-C mRNA were not altered. Moreover, CMO hamster lungs showed less activation of guanylyl cyclase by ANF. These studies demonstrate that lung NPR are downregulated in hamster CMO.
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PMID:Alteration of lung atrial natriuretic peptide receptors in genetic cardiomyopathy. 876 Jan 30

Cloned ANF-sensitive guanylyl cyclase (GC-A) and ANF-sensitive guanylyl cyclase from adrenal cortex differ in their sensitivity to the ANF analogs atriopeptin 1 and urodilatin. To test the hypothesis that these differences are due to different glycosylation, we investigated the effect of the N-glycosylation inhibitor tunicamycin on GC-A. Tunicamycin altered the response of GC-A to atriopeptin 1 and urodilatin, whereas the sensitivity to ANF remained unchanged. These data indicate that agonist specificities of different ANF-sensitive guanylyl cyclases are influenced by carbohydrate moieties.
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PMID:Effect of glycosylation on cloned ANF-sensitive guanylyl cyclase. 876 Oct 9

Depending upon the cofactors Mg2+ or Mn2+, ATP stimulates or inhibits the signal transduction activities of the natriuretic factor receptor guanylate cyclases, ANF-RGC and CNP-RGC: there is stimulation in the presence of Mg2+ and inhibition in the presence of Mn2+. A defined core ATP-regulated modulatory (ARM) sequence motif within the intracellular 'kinase-like' domain of the cyclases is critical for stimulation, but the mechanism of the inhibitory transduction process is not known. In addition, ATP inhibits the basal cyclase activity of a rod outer segment membrane guanylate cyclase (ROS-GC). The mechanism of this inhibitory transduction process is also not known. These issues have been addressed in the present investigation through a program of deletion mutagenesis/expression studies of the cyclases. The study shows that the ATP-mediated inhibitory transduction processes of the natriuretic factor receptor cyclases and of ROS-GC are identical. The ATP-regulated inhibitory domain of all these cyclases resides within the C-terminal segment of the cyclase. This domain is in a different location from the one representing the ATP-stimulatory ARM. The identification of the inhibitory domain in the C-terminal segment of the cyclase indicates that this segment is composed of two separate domains: one representing a catalytic cyclase domain and the other an ATP-regulated inhibitory (ARMi) domain. These findings establish a novel ATP-mediated inhibitory transduction mechanism of the membrane guanylate cyclases which is distinct from that of its counterpart, the stimulatory ATP-mediated hormonal signal transduction mechanism. Thus, they define a new paradigm of guanylate cyclase-linked signal transduction pathways.
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PMID:Distinct inhibitory ATP-regulated modulatory domain (ARMi) in membrane guanylate cyclases. 887 Jun 79

1. In rat aortic rings precontracted with phenylephrine, the beta-adrenoceptor agonist isoprenaline (10 nM to 30 microM) produces greater relaxant effects in preparations with endothelium than in endothelium-denuded preparations. The aim of this study was to determine the mechanisms involved in this effect and in particular investigate the possibility of a synergistic action between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2. Isoprenaline-induced relaxation of rat aortic rings precontracted with phenylephrine was greatly reduced by the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 300 microM) or the soluble guanylate cyclase inhibitors methylene blue (10 microM) or IH-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM) but unaffected by indomethacin (10 microM), a cyclo-oxygenase inhibitor. Similarly, in intact rings, the concentration-response curve of forskolin (10 nM to 1 microM) was shifted to the right upon endothelium removal or treatment with methylene blue. 3. In endothelium-denuded rat aortic rings, isoprenaline-induced relaxation was potentiated by the guanylate cyclase activators atrial natriuretic factor (ANF, 1 to 10 nM) and sodium nitroprusside (SNP, 1 to 10 nM), and to a greater extent in the presence of the cyclic GMP-specific phosphodiesterase (PDE 5) inhibitor, 1,3dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl) pyrazolo [3,4-d] pyrimidin-4-(5H)-one (DMPPO, 30 nM). Relaxation induced by isoprenaline was also potentiated by the cyclic GMP-inhibited PDE (PDE 3) inhibitor cilostamide (100 nM). 4. Intracellular cyclic nucleotide levels were measured either in rat cultured aortic smooth muscle cells or in de-endothelialized aortic rings. In both types of preparation, isoprenaline (5 nM and 10 microM) increased cyclic AMP levels and this effect was potentiated by cilostamide (10 microM), by rolipram, a cyclic AMP-specific PDE (PDE 4) inhibitor (10 microM) and by cyclic GMP-elevating agents (50 nM ANF or 30 nM SNP plus 100 nM DMPPO). In isoprenaline-stimulated conditions, the increase in cyclic AMP induced by rolipram was further potentiated by cilostamide and by cyclic GMP-elevating agents. Cilostamide and cyclic GMP-elevating agents did not potentiate each other, suggesting a similar mechanism of action. 5. We conclude that in vascular smooth muscle (VSM) cells an increase in cyclic GMP levels may inhibit PDE 3 and, thereby, cyclic AMP catabolism. Under physiological conditions of constitutive NO release, and to a greater extent in the presence of the PDE 5 inhibitor DMPPO, cyclic GMP should act synergistically with adenylate cyclase activators to relax VSM.
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PMID:Effects of cyclic GMP elevation on isoprenaline-induced increase in cyclic AMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase 3. 889 66

The distribution and nature of natriuretic peptide receptors (NPR) in the gills of dogfish, Squalus acanthias, were examined by tissue section autoradiography, competition analysis, protein electrophoresis, guanylate cyclase (GC) assays, and molecular cloning. Specific NP binding occurred on the gill filaments, but not on the interbranchial septum or gill arch. The binding was densest on the efferent edge of the gills. Higher resolution light-microscopic examination of emulsion-coated sections showed that specific binding occurred mainly on the secondary lamellae and filament body and not on the arterial circulation. At least two types of NPR were revealed. One is linked to GC since NP binding stimulates the production of cGMP. The GC receptor may be similar to the NPR-B mammalian receptor since only pCNP stimulated cGMP production. The second receptor is not linked to GC and binds the specific ligand C-ANF [rat des(Gln18, Ser19, Gly20, Leu21, Gly22)]. The sequence of a cDNA generated using primers based on conserved regions of vertebrate NPR-C had considerable homology with mammalian and eel NPR-C and eel NPR-D. The presence of GC-linked NPR and NPR-C/ NPR-D suggests that the gills are an important target organ for NP action.
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PMID:Distribution and characterization of natriuretic peptide receptors in the gills of the spiny dogfish, Squalus acanthias. 920 67

Atrial natriuretic peptide (ANP) has previously been suggested to inhibit the production of NO in LPS-activated primary macrophages. The aim of the present study was 1) to examine whether ANP elicits this effect also on macrophage cell lines (RAW 264.7, J774), 2) to elucidate whether ANP is the only natriuretic peptide (NP) inhibiting NO synthesis, 3) to look for the expression of natriuretic peptide receptors (NPR) on macrophages, 4) to consequently determine the type of receptor mediating the ANP effect and 5) to obtain first information on the underlying mechanism. Whereas ANP dose dependently (10(-6)-10(-8) M) inhibited NO synthesis (measured as nitrite accumulation, 20h) in all four types of macrophages (bone marrow derived and peritoneal macrophages; RAW 264.7 and J 774), urodilatin and atriopeptin I displayed only a weak effect restricted to the highest concentration (10(-6) M) employed. Importantly, C-type natriuretic peptide (CNP) showed no NO-inhibitory effect. The lack of effect of CNP was shown not to be due to its lower stability or its missing receptor. Macrophages were shown to express all three natriuretic peptide receptors (NPR-A, NPR-B, NPR-C) using RT-PCR technique. Furthermore, two types of NPR-B seem to be present in macrophages. The effect of ANP was mediated via the guanylate cyclase coupled NPR-A as shown by experiments employing stable cGMP analogs, the NPR-A antagonist HS-142-1, LY-83583, a cGMP inhibitor as well as C-ANF, a specific ligand of the NPR-C. Reduction of nitrite accumulation by ANP was highest when added simultaneously with LPS and abolished when added 12 h after LPS stimulation. In summary, ANP was shown to inhibit NO production of LPS-activated macrophages via cGMP.
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PMID:Effects of different natriuretic peptides on nitric oxide synthesis in macrophages. 932 41

A radioligand-binding assay was established for eel atrial natriuretic peptide (eANP), and ANP receptors were characterised in the eel gill. ANP binding to the gill membrane fraction was saturable with increasing ligand concentrations and was specific to ANP peptides, i.e. eANP, ventricular natriuretic peptide (VNP) and C-type natriuretic peptide (CNP). A Scatchard analysis revealed a single class of high-affinity receptors with a Kd of 59.2 pM and a Bmax of 67.9 fmol/mg protein. The Kd value is within the range of plasma ANP concentration of the eel. Kd and Bmax did not differ between freshwater (FW)- and seawater (SW)-adapted fish. The gill receptors exhibited similar affinity for eANP, eVNP and eCNP, and ANP binding was almost completely displaced by C-ANF, a specific ligand for guanylate cyclase-uncoupled receptors. The presence of this type of receptor (natriuretic peptide receptor (NPR)-C and NPR-D) was also indicated in eel gill by affinity labelling. cGMP production was stimulated by the addition of eCNP but not by eANP and eVNP, and this was observed only in FW eels. Thus, most ANP receptors in eel gill are NPR-C and NPR-D, but a small number of the NPR-B type are also present in FW eels. In addition to the gill, specific ANP receptors were detected in the red body of the swim bladder, the brain, digestive tracts, kidney, head kidney and urinary bladder, in most of which ANP action has been reported. The density of ANP receptors decreased in most tissues after adaptation to SW except the gill, brain, atrium and spleen.
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PMID:Characterisation of natriuretic peptide receptors in eel gill. 937 18

Only C-type natriuretic peptide (CNP) has been identified in primitive elasmobranch fish. CNP is the most conserved molecule in the natriuretic peptide family, suggesting that it is the ancestral type. As a first step to investigating the ancestral type of natriuretic peptide receptors, CNP receptors were characterised in an elasmobranch (dogfish, Triakis scyllia) by radioligand-binding analysis using 125I-[Tyr0]-dogfish (df)CNP. None of the modifications of the CNP molecule that occur at the time of iodination (addition of a Tyr residue at the N-terminus, introduction of iodine into Tyr0 or oxidation of Met17) affect the affinity of dfCNP for the receptors. Neither did oxidation of Met17 decrease the ability of CNP to stimulate cGMP production. In the tissues examined, CNP receptors were densest in the gill cells followed by the intestine, interrenal gland and rectal gland, all of which are involved in osmoregulation in elasmobranchs. CNP-stimulated guanylate cyclase (GC) activity was highest in the interrenal gland, intestine, brain and rectal gland, followed by the gill cells. Since the gill cells seem to contain both GC-coupled and uncoupled receptors, this tissue was used to characterise dogfish CNP receptors. Scatchard analysis of the saturation isotherm revealed two classes of binding site: one has a Kd of 24.0 pM and Bmax of 59.9 fmol/mg protein, and the other has low affinity (Kd > 1 nM) and high capacity (Bmax > 200 fmol/mg protein). The higher-affinity binding sites may represent GC-uncoupled receptors, because C-ANF, a specific ligand for GC-uncoupled receptors, almost completely displaced CNP binding. Affinity-labelling experiments showed that dogfish receptors have molecular masses of about 90, 170 and 340 kDa, and CNP binding to the former two receptors is inhibited by C-ANF. After reduction with 2-mercaptoethanol, most 170 kDa labelling was shifted to 90 kDa. It is concluded that GC-uncoupled receptors in the dogfish gill have higher molecular mass than those of mammals and eel (about 65 kDa), and are present mostly as monomers even in non-reducing conditions. However, a small population of GC-coupled receptors is also present, as demonstrated by an increase in cGMP production.
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PMID:Characterisation of C-type natriuretic peptide receptors in the gill of dogfish Triakis scyllia. 949 42


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