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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial, brain-type, and C-type natriuretic peptides (ANP, BNP, and CNP) act via receptors with intrinsic guanylate cyclase activity. The A-type and B-type ANP receptors are selectively activated by ANP and CNP, respectively. The anterior pituitary is a site of ANP production and action, suggesting a local regulatory function, and this may also hold true for CNP which is found at its highest tissue concentrations in the anterior pituitary. Here we show that these peptides all cause dose-dependent increases in cGMP accumulation in alpha T3-1 cells (a gonadotrope-derived cell line), GH3 cells, and in primary cultures of rat pituitary cells. The response to CNP is particularly robust in alpha T3-1 cells (59 +/- 9-fold increase, EC50 14 +/- 3 nM), and the rank order of potency in alpha T3-1 cells and primary cultures (CNP >> ANP > BNP) is suggestive of action exerted via B-type receptors. Although CNP did not alter GnRH-stimulated LH release or [3H]inositol phosphate accumulation, GnRH reduced CNP-stimulated cGMP accumulation dose dependently (EC50 approximately 0.1 nM). This inhibition reflects the ability of GnRH to shift the CNP dose-response curve rightward (increasing the EC50 for CNP action approximately 10-fold both with and without 3-isobutyl-1-methylxanthine). The inhibitory effect was not blocked by omission of extracellular Ca++ nor mimicked by the Ca++ ionophore A23187 but was mimicked by a protein kinase C (PKC)-activating phorbol ester (which had a comparable effect to GnRH on the EC50 for CNP action). The data imply that CNP rather than (or in addition to) ANP may have a local regulatory function within the pituitary, that although its role is currently unknown it may involve functional interaction with GnRH in gonadotropes, and that the effect of GnRH on CNP action may be PKC-mediated. Moreover, we suggest that alpha T3-1 cells may be a useful model for investigation of the cross-talk between the B-type natriuretic peptide receptor-regulated signal transduction pathway and the Ca++/PKC pathway activated by ligand-stimulated hydrolysis of inositol phospholipids.
...
PMID:Cyclic guanosine monophosphate production in the pituitary: stimulation by C-type natriuretic peptide and inhibition by gonadotropin-releasing hormone in alpha T3-1 cells. 768 40

In bovine lung membranes, atrial natriuretic peptide (ANP) showed temperature-dependent binding to guanylate cyclase-natriuretic peptide receptor (NPR-GC). Photoaffinity labeling of the receptors with 4-azidobenzoyl (AZB)-125I-ANP and competitive binding studies with 125I-ANP, ANP, and atriopeptin I (API) revealed that NPR-GC was detected as the predominant ANP-binding protein at 0 degrees C, whereas at 37 degrees C natriuretic peptide clearance receptor (NPR-C) was detected as the predominant protein. The ratio of NPR-GC and NPR-C was 89:11 at 0 degrees C for 40 min, respectively, whereas 6:94 at 37 degrees C. AZB-125I-ANP bound to NPR-GC dissociated from the binding site within 5 min at 37 degrees C but not at 0 degrees C, whereas ANP bound to NPR-C did not dissociate from the binding site at 0 and 37 degrees C. The dissociated AZB-125I-ANP rapidly rebound to NPR-GC at 37 degrees C but not to NPR-C, and the dissociated NPR-GC was capable of binding. Some AZB-125I-ANP was hydrolyzed by a membrane-bound proteinase(s). Phosphoramidon inhibited the hydrolysis of AZB-125I-ANP. Thus, the dissociated AZB-125I-ANP rebound to NPR-GC and NPR-C. These results suggest that usually intact ANP repeatedly binds to NPR-GC until hydrolysis. Furthermore, the majority of ANP bind to NPR-GC before binding to NPR-C under physiological temperature.
...
PMID:Interaction of atrial natriuretic peptide with its receptors in bovine lung membranes. 770 15

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

Natriuretic peptides are hormones that play an important role in the cardiovascular control of mammalian and non-mammalian vertebrates. They have been classified into four groups. Of these, ANP (atrial natriuretic peptide), BNP (brain atriuretic peptides), CNP (C-type natriuretic peptide) are detected in cardiac and non cardiac tissues of all vertebrates; while VNP (ventricular natriuretic peptide) has been isolated only from the fish ventricle. All peptides have shown a high degree of sequence homology. The expression of the three principal types of natriuretic peptide (ANP, BNP and CNP) in cardiac tissues is developmentally and functionally regulated in a highly tissue-specific manner. Three types of natriuretic peptide receptors have been identified in numerous target tissues. Two receptors are transmembrane guanylyl cyclases (ANPR-A and ANPR-B) that mediate biological effects of natriuretic peptides; the third one (ANPR-C) has no guanylyl cyclase and is called "clearance receptor." The presence of natriuretic peptide binding sites in the heart suggests new aspects of paracrine control of cardiac function. A relevant localization of natriuretic peptide receptors was found in those cardiac regions particularly suitable for monitoring blood volume and pressure oscillations such as the inflow tract and the outflow tract. For example, in birds (quail) the highest levels of natriuretic peptide receptors were detected in the inflow tract represented by the vena cava. In both fish and birds, the outflow chamber, the bulbus cordis, had a high number of natriuretic peptide binding sites. In mammals, a remarkable concentration of natriuretic peptide receptors was also observed in the coronary vessels. This zoning of cardiac natriuretic peptide receptors indicates an intracardiac action of the hormones and adds a humoral dimension to the morphofunctional design of the vertebrate heart.
...
PMID:Cardiac distribution of the binding sites for natriuretic peptides in vertebrates. 774 80

The distribution and nature of natriuretic peptide binding sites was determined in the gills of the toadfish, Opsanus beta. Specific 125I-labeled rat atrial natriuretic peptide (rANP) and 125I-labeled porcine C-type natriuretic peptide (pCNP) binding sites were observed on the afferent and efferent filamental arteries and lamellar arterioles, and on the marginal channels of the secondary lamellae. In both section autoradiography and competition assays, the binding of both ligands was completely displaced by 1 microM rANP and 1 microM pCNP, but residual binding was observed with 1 microM of the type C natriuretic peptide receptor (NPR-C)-specific ligand C-ANF. Electrophoresis of gill membranes cross-linked with 125I-rANP showed a major band at 75 kDa and a fainter band at 140 kDa. Both rANP and pCNP significantly stimulated the production of cGMP above basal levels; C-ANF had no stimulatory effect. These data show that the intrafilamental gill vasculature of toadfish contains a major population of natriuretic peptide receptors very similar to mammalian clearance receptors and a smaller population of receptors that are linked to a membrane-bound guanylate cyclase.
...
PMID:Localization and analysis of natriuretic peptide receptors in the gills of the toadfish, Opsanus beta (teleostei). 781 Jul 50

Guanylyl cyclase-A (GC-A), a receptor for A-type natriuretic peptide (ANP), contains an extracellular ligand-binding domain, a single transmembrane domain, and intracellular protein kinase-like and cyclase catalytic domains. Expression of the putative cyclase catalytic region (HCAT) resulted in the formation of an active enzyme that migrated as a homodimer on gel filtration columns; treatment with sodium trichloroacetate caused dissociation of the dimer and a loss of cyclase activity. Co-transfection of HCAT and full-length GC-A led to elevated basal intact cell cGMP concentrations and increased cell homogenate guanylyl cyclase activity. However, atrial natriuretic peptide-induced elevations of cGMP and cyclase activity were inhibited by the introduction of HCAT. Alanine scanning mutagenesis of highly conserved residues within HCAT identified one mutation (D893A) that destroyed enzyme activity but not the ability of the mutant subunit to form homodimers. The mutant subunit inhibited the cyclase activity of wild-type HCAT (approximately 70%) as well as that of full-length GC-A (approximately 85%) in co-expression studies where the amount of wild-type HCAT or full-length GC-A was not altered. Unlike co-transfection with wild-type HCAT, co-transfection of HCA-TD893A and GC-A did not result in elevated basal intact cell cGMP concentrations. For the first time we describe deletion and point mutations within the plasma membrane family of guanylyl cyclase receptors that result in the formation of effective dominant negative proteins.
...
PMID:Dominant negative mutations of the guanylyl cyclase-A receptor. Extracellular domain deletion and catalytic domain point mutations. 781 5

We describe the isolation of a 3,276 base pair cDNA for the bovine natriuretic peptide receptor-B (NPR-B). Expression of this clone in Cos-P cells demonstrates that it encodes an agonist-dependent guanylyl cyclase. Porcine CNP stimulates the activity of this receptor up to 200-fold with an ED50 of 12 +/- 2 nM, whereas brain natriuretic peptide C-type natriuretic peptide (CNP) and atrial natriuretic factor (ANF) are less efficacious. In addition, ligand binding studies indicate that this receptor exhibits the pharmacology appropriate for the bovine NPR-B. CNP binds to Cos-P cell membranes expressing this clone with a Kd of 13 +/- 1 pM, and natriuretic peptides compete for [125I]-CNP binding with a rank order of pCNP > pBNP > rANF. Thus, the expressed receptor-guanylyl cyclase exhibits the expected pharmacological profile for ligand binding and cyclase activation of the bovine NPR-B receptor.
...
PMID:Cloning and functional expression of the bovine natriuretic peptide receptor-B (natriuretic factor R1c subtype. 784 91

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


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

---