Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natriuretic peptide receptor-C (NPR-C) constitutes greater than 95% of the natriuretic peptide binding sites in vivo. This cell surface glycoprotein is a disulfide-linked homodimer with a subunit molecular weight of 68,000. Two sources and types of ANP affinity-purified human NPR-C were used to map disulfide linkages and glycosylation sites of this receptor by mass spectrometry: the extracellular domain obtained by papain cleavage of a receptor-IgG fusion protein expressed in Chinese hamster ovary cells, and a baculovirus/Sf9-expressed cytoplasmic truncation mutant in which 34 of 37 cytoplasmic domain amino acids were deleted. Two intramolecular disulfide bonded loops were found in the 435 amino acid extracellular domain (C63-C91, C168-C216). The juxtamembrane residues C428 and C431 are involved in homodimer formation, confirmed by site-directed mutagenesis of full-length NPR. Three of the four potential Asn-linked glycosylation sites are occupied: N41 (complex), N248 (high mannose), and N349 (complex; partial occupancy). These data describe the intra- and intermolecular linkages in NPR-C, providing a model for the homologous guanylyl cyclase receptors, NPR-A and NPR-B; both of the cyclase receptors likely contain the first amino-terminal 29 amino acid loop, but only NPR-A possesses the second 49 amino acid loop in common with NPR-C.
 ...
PMID:The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer. 772 88

Natriuretic peptides modulate systemic blood pressure, diuresis and natriuresis through the stimulation of cGMP production by guanylyl cyclase-coupled natriuretic peptide receptor-A and -B (GC-A and GC-B). A novel isoform of GC-A, GC-A1, has been identified which is the result of differential splicing of a new exon, 5a. This 9 bp sequence is predicted to add proline-cysteine-glutamine to the extracellular juxtamembrane region of the receptor protein. Transcripts for GC-A1 are expressed primarily in the renal papilla and adrenal. In these tissues, its abundance relative to GC-A was 1-2.5% as assessed by quantitative PCR.
 ...
PMID:A novel guanylyl cyclase-A isoform: rat GC-A1 identification and mRNA localization to renal papilla and adrenal. 773 86

Guanosine 5'-(gamma-thio)triphosphate (GTP gamma S) exhibited a modulatory role in the catalytic activation of guanylate cyclase-A/atrial natriuretic factor receptor (GC-A/ANF-R) in the plasma membrane preparations of murine Leydig tumor (MA-10) cells. Both atrial natriuretic factor (ANF) and GTP gamma S synergistically stimulated the guanylate cyclase (GC) activity of GC-A/ANF-R in a dose- and time-related manner. Other nucleotides and their analogs such as ATP, adenosine 5'-(gamma-thio)triphosphate, adenosine 5'-(beta,gamma-imino)triphosphate, GDP, and guanosine 5'-(2-O-thiodiphosphate) (100 microM each) did not show any discernible effect on GC catalytic activity of GC-A/ANF-R. A significant stimulation of GC activity was observed in the presence of mastoparan, AlF4-, and benzalkonium chloride. The saturation binding assay of [35S]GTP gamma S showed the dissociation constant (Kd) of 2.3 x 10(-9) M and the binding capacity (Bmax) of 76 pmol/mg protein in the plasma membrane preparations of MA-10 cells. ANF increased the [35S]GTP gamma S-binding capacity, however, without affecting its affinity constant. Pretreatment of plasma membranes with antibodies against Gs alpha subunit attenuates the GTP gamma S-stimulated GC activity, whereas antibodies against Gi alpha subunit enhanced the stimulatory effect of GTP gamma S on GC catalytic activity of GC-A/ANF-R. However, the antibodies against Go alpha subunit did not show any effect on GC activity. These results provide the evidence that both Gs and Gi subunits of G-proteins seem to be involved in the regulation of GC catalytic activity of GC-A/ANF-R in the plasma membranes of MA-10 cells.
 ...
PMID:Catalytic activation of guanylate cyclase/atrial natriuretic factor receptor by combined effects of ANF and GTP gamma S in plasma membranes of Leydig tumor cells: involvement of G-proteins. 784 Jun 42

Subtype switching of natriuretic peptide receptor (NPR) during in vitro culture of rat chondrocytes was demonstrated by polymerase chain reaction (PCR) analysis, receptor binding assay, and the cGMP formation method. NPR-B was the predominant form in the receptor guanylate cyclase family (i.e. NPR-A and NPR-B) in both rat xiphoid cartilage and in its cultured cells. However, the chondrocytes began to express NPR-C at high levels when cultured in vitro and NPR-C became the major form (maximal binding capacity: 450 fmol/mg of protein) of NPR in the cultured cells. The abundantly expressed NPR-C had no effect on adenylate cyclase activity or proliferation of chondrocytes.
 ...
PMID:Subtype switching of natriuretic peptide receptors in rat chondrocytes during in vitro culture. 785 78

1. The renal actions of natriuretic peptides are dictated by the distribution of guanylyl cyclase-linked (NPRA and NPRB) and non-guanylyl cyclase-linked (NPRC) receptors. Natriuretic peptide receptors have previously been distinguished on the basis of their differential affinity for peptide fragments and analogues; however, most of the available ligands are not fully selective. We have used the specific guanylyl cyclase-linked receptor antagonist, HS-142-1, to investigate the differential distribution of natriuretic peptide receptor subtypes in the human, bovine and rat kidney. 2. Specific, high affinity 3-([125I]-iodotyrosyl)-rat-ANP-(1-28)([125I]-rANP1-28) binding sites were identified in all three species, localized to glomeruli, inner medulla, intrarenal arteries and regions in the outer medulla corresponding to vasa recta bundles. Binding sites were also identified in the smooth muscle lining of the hilar region in the bovine and rat kidney. 3. In the rat, [125I]-rANP1-28 binding was inhibited by unlabelled peptide sequences with a rank order of potency (rANP1-28 > pCNP1-22 > C-ANP4-23). The glomeruli exhibited a heterogeneous population of binding sites, C-ANP4-23 and pCNP1-22 producing a significantly better fit to a two component inhibition curve compared to the single component curve for rANP1-28. 4. Competitive inhibition experiments with the receptor selective ligands, C-ANP4-23 and HS-142-1, suggested that, like the rat, human and bovine glomeruli possessed a heterogeneous population of binding sites, whilst those in the inner medulla and intrarenal arteries of all three species represented a homogeneous population. Rat glomeruli exhibited a high proportion (>80%) of the NPRc receptor subtype whereas in human and bovine glomeruli this receptor represented less than 20% of the total population, the majority of binding sites being HS-142-1-sensitive.5. C-ANP4-23 exhibited a significantly higher inhibitory potency for binding sites in rat glomeruli compared to those in human and bovine kidney whilst HS-142-1 was significantly more potent in the rat and bovine kidney compared to man. No evidence was found to suggest the presence of a renal NPRBreceptor subtype.6. The relative density, affinity and proportion of natriuretic receptor subtypes in the kidney exhibit significant species differences. HS-142-1 may be a valuable tool in further elucidating the localization and function of these receptors, but heterogeneity between species should be considered when selecting experimental models.
 ...
PMID:Identification of renal natriuretic peptide receptor subpopulations by use of the non-peptide antagonist, HS-142-1. 785 88

To test the hypothesis that expression of atrial natriuretic peptide (ANP)-receptor genes is modified to provide a compensatory mechanism against hypoxic pulmonary hypertension, steady state mRNA levels for the ANP-A receptor (or guanylate cyclase-A; ANPAR), ANP-B receptor (or guanylate cyclase-B; ANPBR), and ANP-clearance receptor (ANPCR) were quantitated by Northern blot and slot-blot analysis in lung, kidney, spleen, and liver of hypoxia-adapted rats and air controls. Exposure of rats to short-term (48 h) and chronic (4 wk) hypoxia (10% O2, 1 atm) did not affect lung ANPAR-mRNA levels. Lung ANPBR-mRNA levels were unchanged by short-term hypoxia but selectively increased (approximately twofold) by chronic hypoxia. ANPCR-mRNA levels were selectively and significantly downregulated by 48-h and 4-wk hypoxia in lung but were unchanged or upregulated in other tissues. Lung ANPCR gene transcription, assessed by nuclear-runoff analysis, was decreased by hypoxia. These data support the conclusion that altered pulmonary ANP-receptor gene expression modulates the development of hypoxic pulmonary hypertension.
 ...
PMID:Selective downregulation of ANP-clearance-receptor gene expression in lung of rats adapted to hypoxia. 786 53

Atrial natriuretic peptide (ANP) regulates glomerular hemodynamics by interaction with biologic receptors (GC-A/ANP) that possess particulate guanylyl cyclase activity. In a previous study we have shown a developmental difference in glomerular response to ANP where preweaned glomeruli produced significantly less extracellular cGMP in response to ANP. Because of the possibility that functional differences in the ANP biologic receptor might exist during development, further characterization of GC-A/ANP receptor response in glomeruli of developing rats was done using a structural analogue of ANP. A71915 (Abbott Laboratories) is a structural analogue of ANP which has been shown to inhibit activation of ANP receptor-associated guanylyl cyclase in vascular smooth muscle cells. The purpose of this study was to investigate the ability of A71915 to inhibit ANP-stimulated cGMP response in isolated glomeruli of adult and preweaned rats. Isolated glomeruli from preweaned or adult rat kidneys were preincubated for 15 min with A71915 (10(-5) M) prior to addition of ANP (up to 10(-6) M). Glomerular response of production of intracellular and extracellular cGMP was measured by radioimmunoassay. Adult glomeruli produced significantly greater amounts of extracellular cGMP compared to preweaned glomeruli for concentrations of ANP > or = 10(-9) M. Infant glomeruli had a significant decrease in the production of ANP-stimulated intracellular cGMP in the presence of A71915 (10(-5) M), whereas extracellular cGMP production was unchanged. In contrast both ANP-stimulated intracellular and extracellular cGMP were significantly decreased by A71915 in adult glomeruli. These results demonstrate the maturation of the glomerular response to ANP.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Maturation of A71915-dependent inhibition of atrial natriuretic peptide-stimulated cyclic GMP production in isolated rat glomeruli. 787 95

The most potent known agonist for the natriuretic peptide receptor-B (NPR-B)/guanylyl cyclase-B is C-type natriuretic peptide (CNP). A homologous ligand-receptor system consists of atrial natriuretic peptide (ANP) and NPR-A/guanylyl cyclase-A. A third member of this family is NPR-C, a non-guanylyl cyclase receptor. Monoclonal antibodies were raised against NPR-B by immunizing mice with a purified receptor-IgG fusion protein consisting of the extracellular domain of NPR-B and the Fc portion of human IgG-gamma 1. One monoclonal antibody, 3G12, did not recognize NPR-A or NPR-C and bound to human and rat NPR-B. CNP binding to NPR-B and stimulation of cGMP synthesis were inhibited by 3G12. With cells isolated from either the media or adventitia layers of rat thoracic aorta, 3G12 did not interfere with ANP-stimulated cGMP synthesis, but it inhibited CNP-stimulated cGMP levels in cells from both layers. CNP (IC50 = 10 nM) and ANP (IC50 = 1 nM) caused relaxation of phenylephrine-contracted rat aortic rings. 3G12 caused a marked increase in the IC50 for CNP, from 10 nM to 140 nM, but failed to affect ANP-mediated relaxation. Therefore, our results for the first time demonstrate that CNP relaxes vascular smooth muscle by virtue of its binding to NPR-B.
 ...
PMID:Natriuretic peptide receptor-B (guanylyl cyclase-B) mediates C-type natriuretic peptide relaxation of precontracted rat aorta. 787 38

Specific binding of iodinated natriuretic peptides 125I-ANP and 125I-CNP was examined in the gill of the Atlantic hagfish Myxine glutinosa by tissue section autoradiography, saturation and competition analysis of binding to membrane preparations, affinity cross-linking, followed by SDS-PAGE and guanylate cyclase assays. Autoradiographs showed specific, saturable binding on the respiratory lamellar epithelium. In vitro analysis of the binding sites demonstrated that 125I-ANP bound to two receptor sites with the same affinity (Kd = 15.4 +/- 1.6 pmol l-1; Bmax = 45.9 +/- 3.0 fmol mg-1 protein). 125I-CNP bound to high- and low-affinity receptor sites; variables for the high-affinity site (Kd = 12.9 +/- 4.7 pmol l-1; Bmax = 23.4 +/- 6.5 fmol mg-1 protein) did not differ from those for the 125I-ANP sites. The low-affinity site had an apparent Kd and Bmax of 380 +/- 80 pmol l-1 and 120 +/- 21 fmol mg-1 protein, respectively. All receptors had an apparent molecular mass of approximately 150 kDa, with no indication of a mammalian type NPR-C at a lower apparent molecular mass. 1 nmol l-1 unlabelled rANP and 20 and 30 nmol l-1 unlabelled pCNP and C-ANF, respectively, competed for 50% of 125I-ANP sites. 0.1 nmol l-1 rANP and pCNP and 8 nmol l-1 C-ANF competitively inhibited 50% of 125I-CNP binding. Both rANP and pCNP stimulated cyclic GMP production, although rANP was a more potent stimulator than was pCNP. C-ANF did not stimulate cyclic GMP production. These data suggest the existence of an ANP guanylate-cyclase-linked receptor similar to the mammalian NPR-A and an ANP/CNP receptor that may be similar to, although not structurally homologous with, the mammalian NPR-C clearance receptor.
 ...
PMID:Localisation and characteristics of natriuretic peptide receptors in the gills of the Atlantic hagfish Myxine glutinosa (Agnatha). 789 Oct 31

The membrane-bound form of guanylate cyclase represents a biologically active atrial natriuretic factor receptor (GC/ANF-R). We have constructed genomic map of murine GC-A/ANF-R gene using 17 different restriction endonucleases. The restriction mapping results indicated that murine GC-A/ANF-R gene is approximately 20 kb single copy with multiple smaller exons and bigger introns. The Kpn I and Sfu I restriction digests produced 27 kb and 35 kb fragments, respectively, which hybridized with 5'- and 3'-flanking cDNA probes. Both of these fragments should cover the entire murine GC-A/ANF-R genomic sequences. The southern blot hybridization of genomic DNA from human, rat and mouse, using murine 5'-flanking cDNA probe indicated the presence of higher variant sequences in the 5'-flanking region of GC-A/ANF-R gene among different species. The noncoding 5'-flanking probe (350 bp) hybridized only to mouse genomic DNA but not to the human or rat DNA. These sequence variations located in the noncoding 5'-flanking region of GC-A/ANF-R gene may explain the divergent evolutionary development among different species. This is the first demonstration of the restriction endonuclease digestion and genomic mapping of murine GC-A/ANF-R gene which should be valuable to the understanding of its regulation and function.
 ...
PMID:Genomic restriction endonuclease analysis and mapping of murine guanylate cyclase-A/atrial natriuretic factor receptor gene. 790 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>