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)

Natriuretic peptides modulate vasorelaxation, diuresis, and natriuresis through the stimulation of cGMP production by the guanylate cyclase-coupled natriuretic peptide receptors, GC-A and GC-B. We used reverse transcription-polymerase chain reaction to determine the distribution of mRNA encoding both receptors in rat tissues. GC-A and GC-B transcripts were detected in all peripheral and neural tissues examined. Since the atrial natriuretic peptide gene is expressed in all these tissues, our widespread detection of GC-A and GC-B mRNAs now suggests that natriuretic peptides may act as endocrine and paracrine hormones as well as neurotransmitters via both GC-A and GC-B receptors.
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PMID:Widespread co-localization of mRNAs encoding the guanylate cyclase-coupled natriuretic peptide receptors in rat tissues. 136 29

HS-142-1, a specific nonpeptide antagonist for the atrial natriuretic peptide (ANP) receptor, equally blocked rat ANP (rANP)-, porcine brain natriuretic peptide-, or porcine C-type natriuretic peptide-stimulated GMP production in cultured bovine aortic smooth muscle (BASM) and bovine aortic endothelial (BAE) cells in a concentration-dependent fashion, at concentrations of 1-300 micrograms/ml. But, even at 300 micrograms/ml, HS-142-1 only weakly inhibited the specific binding of 125I-rANP to the BASM and BAE cells, where only a small portion of the binding sites are linked to guanylyl cyclase. Further, with BAE cell membranes, HS-142-1 recognized only the 135-kDa ANP receptor, which is thought from 125I-rANP affinity cross-linking studies to be the guanylyl cyclase-linked receptor. HS-142-1 also, if anything, inhibited the labeling of 135-kDa ANP receptors in the affinity cross-linking studies with BASM membranes, suggesting that a major portion of the 135-kDa ANP receptors are HS-142-1 insensitive and only a small portion of the 135-kDa ANP receptors are responsible for the blockade by HS-142-1 of GMP production in BASM cells. At a concentration of 100 micrograms/ml, HS-142-1 reversibly prevented ANP-induced relaxation of the isolated rabbit thoracic aorta induced to contract with 3 x 10(-7) M phenylephrine, but not the relaxation induced by sodium nitroprusside, isoproterenol, or papaverine. These results suggest that HS-142-1 specifically inhibits natriuretic peptide-induced vasorelaxation through the blockade of guanylyl cyclase-linked natriuretic peptide receptors. HS-142-1 thus will be a powerful tool for understanding the physiological roles, in vasculature, of natriuretic peptides, which contribute to the homeostasis of blood pressure and intravascular volume.
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PMID:Inhibition by HS-142-1, a novel nonpeptide atrial natriuretic peptide antagonist of microbial origin, of atrial natriuretic peptide-induced relaxation of isolated rabbit aorta through the blockade of guanylyl cyclase-linked receptors. 136 44

Up to now, members of the natriuretic peptide family have usually been determined by radioimmunoassays using antibodies more or less specific for the distinct peptides so far identified. However, natriuretic peptides differing significantly in their amino acid sequence from the one against which the antibody has been raised cannot be determined by this means, and still unknown natriuretic peptides cannot be detected. We therefore developed a new bioassay system sensitive to all members of the natriuretic peptide family by taking advantage of the biological activity of these hormones, the activation of the guanylate cyclase/cyclic GMP system. In this assay, cultured cells are incubated with the natriuretic peptides, and the amount of cyclic GMP produced by the cells is determined by radioimmunoassay. From the relative stimulation of the cellular cyclic GMP production, the concentration of natriuretic peptides in the sample is determined after calibration with synthetic atrial natriuretic peptide. For a qualitative identification of the various peptides, the bioassay is combined with a reversed-phase HPLC step. Using cultured bovine aortic endothelial or bovine kidney epithelial cells for the bioassay, we achieved detection limits of 1 fmol or 50 fmol, respectively, for human atrial as well as brain natriuretic peptide. Intra-assay coefficients of variation of 4.3% (aortic endothelial cells, at 0.65 nmol/l peptide) and 5.8% (kidney epithelial cells, at 6.5 nmol/l peptide) were obtained. The total content of natriuretic peptides as well as the amounts of the individual natriuretic peptides following HPLC separation were determined in extracts of human atria obtained at aortocoronary bypass operations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitative determination of natriuretic peptides in human biological samples with a bioassay using cultured cells. 136 55

Dopamine accumulation in hypothalamic cells by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was analyzed using newborn rat hypothalamic cells in culture. Both ANP and BNP caused a dose-dependent increase in [3H]-dopamine accumulation in the cells. ANP increased [3H]-dopamine accumulation significantly within 20 min. The effects of ANP and BNP on dopamine accumulation paralleled an increase in intracellular cGMP concentration. (Bu)2-cGMP and sodium nitroprusside, a stimulator of the soluble form of guanylate cyclase, also enhanced [3H]-dopamine accumulation. ANP had no effect on efflux of [3H] radioactivity after [3H]-dopamine uptake. These results suggest that a change in cGMP is one of the intermediate steps in dopamine accumulation in hypothalamic cells by ANP and BNP.
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PMID:Atrial and brain natriuretic peptides enhance dopamine accumulation in cultured rat hypothalamic cells including dopaminergic neurons. 138 13

Atrial natriuretic factor (ANF) is released from the cardiac atrium in response to stretch and acts through receptors to cause an increase in urinary flow and sodium excretion, vasodilatation, and a reduction in blood volume. Recently, two new natriuretic peptides, brain natriuretic peptide (BNP) and C-type natriuretic peptide (C-typeNP), have been isolated, and three different natriuretic peptide receptors have been identified. Two of the receptors, ANP-RGC(A) and ANP-RGC(B), mediate biologic actions. The natural ligand of ANP-RGC(A) is ANF, whereas that of ANP-RGC(B) is C-typeNP. In view of clear differences in ligand specificity and tissue distribution of these receptors, it has been proposed that ANF and its receptor, ANP-RGC(A), and C-typeNP and its receptor, ANP-RGC(B), represent two distinct natriuretic peptide regulatory systems. Whether a separate system exists that incorporates BNP awaits clarification of its natural receptor that mediates a biologic action. The third receptor, ANP-Rc, binds all three natriuretic peptides. Its messenger RNA lacks the guanylyl cyclase sequence present in the mRNA of the other natriuretic peptide receptors, suggesting that the principal function of ANP-Rc is to remove natriuretic peptides from the circulation, that is, to regulate plasma levels of the natriuretic peptides. However, ANP-Rc may also mediate a biologic effect. These findings raise several intriguing questions about the functional role of this family of natriuretic peptides.
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PMID:The natriuretic peptides and their receptors. 144 67

The natriuretic peptide receptors (NPRs) are a family of three cell surface glycoproteins, each with a single transmembrane domain. Two of these receptors, designated NPR-A and NPR-B, are membrane guanylyl cyclases that synthesize cGMP in response to hormone stimulation. The third receptor, NPR-C, has been reported to function in the metabolic clearance of ligand and in guanylyl cyclase-independent signal transduction. We engineered three chimeric proteins consisting of the natriuretic peptide receptor extracellular domains fused to the Fc portion of human IgG-gamma 1. These molecules provide material for detailed studies of the human receptor's extracellular domain structure and interaction with the three human natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type-C natriuretic peptide (CNP). The homodimeric fusion proteins, designated A-IgG, B-IgG, and C-IgG, were secreted from Chinese hamster ovary cells and purified by protein-A affinity chromatography. We present here the primary characterization of these fusion proteins as represented by the intrinsic hormone affinities measured by saturation binding and competition assays. The dissociation constant of 125I-ANP for A-IgG was 1.6 pM and for C-IgG, 1.2 pM. The dissociation constant of 125I-Y0-CNP (CNP with addition of tyrosine at the amino terminus) for B-IgG was 23 pM. The rank order of potency in competitive binding for A-IgG was ANP greater than BNP much greater than CNP, whereas for B-IgG the ranking was CNP much greater than ANP greater than BNP. For C-IgG, we observed ANP greater than CNP greater than or equal to BNP. These data demonstrate that the receptor-IgG fusion proteins discriminate among the natriuretic peptides in the same manner as the native receptors and provide a basis for future structural studies with these molecules. The purified fusion proteins have a variety of potential applications, one of which we illustrate by a solid phase screening assay in which rabbit sera from a series of synthetic-peptide immunizations were titered for receptor reactivity and selectivity.
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PMID:Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera. 166 Apr 65

The natriuretic peptides are hormones that can stimulate natriuretic, diuretic, and vasorelaxant activity in vivo, presumably through the activation of two known cell surface receptor guanylyl cyclases (ANPR-A and ANPR-B). Although atrial natriuretic peptide (ANP) and, to a lesser extent, brain natriuretic peptide (BNP) are efficient activators of the ANPR-A guanylyl cyclase, neither hormone can significantly stimulate ANPR-B. A member of this hormone family, C-type natriuretic peptide (CNP), potently and selectively activated the human ANPR-B guanylyl cyclase. CNP does not increase guanosine 3',5'-monophosphate accumulation in cells expressing human ANPR-A. The affinity of CNP for ANPR-B is 50- or 500-fold higher than ANP or BNP, respectively. This ligand-receptor pair may be involved in the regulation of fluid homeostasis by the central nervous system.
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PMID:Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). 167 77

We characterized in membranes from the human neuroblastoma cell line NB-OK-1, an ANP-R1 receptor (Mr 130 kDa) for the atrial natriuretic peptide (ANP). This receptor recognized biologically active forms of ANP with high affinity but showed no affinity for truncated ANP forms. It was functional in that binding correlated with guanylate cyclase activation (a 2-fold increase in Vmax) with the following rank order of potency: rat ANP-(99-126) greater than human ANP-(99-126) greater than human ANP-(102-126) greater than porcine BNP (brain natriuretic peptide). The enzyme required free Mn2+ in addition to the Mn-GTP substrate (Km of about 0.3 mM for both basal and ANP-stimulated activity). In the presence of dithiothreitol, the dose-response curve of guanylate cyclase activation was shifted rightward by a factor of 30. ANP-R1 receptors were upregulated through protein synthesis in cells exposed to 1 mM carbamylcholine or 1 mM dibutyryl cyclic AMP for 8-24 h (ANP was ineffective).
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PMID:Characterization and regulation of atrial natriuretic peptide (ANP)-R1 receptors in the human neuroblastoma cell line NB-OK-1. 168 Jul 22

Heat-stable enterotoxin (STa) produced by Escherichia coli induces intestinal secretion in mammals by binding to the brush border membrane of the small intestine and activating guanylyl cyclase. We report here the cloning and expression of a cDNA encoding the human receptor for STa. The receptor contains both an extracellular ligand binding site and a cytoplasmic guanylyl cyclase catalytic domain, making it a member of the same receptor family as the natriuretic peptide receptors. Stable mammalian cell lines over-expressing the STa receptor specifically bind 125I-STa (Kd approximately 1.0 nM) and respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels. Sequence comparisons between the human and the rat STa receptors show less conservation in the extracellular domain than similar comparisons of natriuretic peptide receptors. This divergence may indicate important species differences in ligand-receptor interaction.
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PMID:Primary structure and functional expression of the human receptor for Escherichia coli heat-stable enterotoxin. 168 Aug 54

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


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