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)

The character of natriuretic peptide receptors (NPRs) in the kidney and aortae of the Atlantic hagfish Myxine glutinosa was determined and compared with that of NPRs in hagfish gills. The relationship of hagfish kidney and aortic NPRs with NPRs from higher vertebrates was also examined. Iodinated atrial and C-type natriuretic peptides (NPs) (125I-ANP, 125I-CNP) were used in tissue section autoradiography, competition studies and guanylate cyclase (GC) assays. Rat atrial and porcine C-type NPs (rANP, pCNP) and rat des[Gln18, Ser19, Gly20, Leu21 Gly22]ANP-(4-23)-NH2 (C-ANF, which binds to the mammalian and teleost 'clearance' receptor, NPR-C), were used as competing ligands. 125I-ANP binding sites were observed on both aortae and on the glomeruli, neck segments and archinephric ducts of the kidney. 4.0 nmol l-1 rANP competed for 50% of 125I-ANP glomerular sites. 125I-CNP did not visibly bind to any of the tissues, but 300 nmol l-1 pCNP competed for 50% of 125I-ANP glomerular sites. C-ANF failed to compete for 125I-ANP sites. rANP and pCNP stimulated cyclic GMP production in kidney membrane preparations, but C-ANF did not, demonstrating that the hagfish kidney NPR is GC-linked. This study suggests that a predominant population of ANP-like receptors, similar to the mammalian NPR-A, exists in the myxinoid aortae and kidney tissue. However, no detectable population of a receptor that binds all NPs, such as is present in the hagfish gill, nor an NPR similar to the NPR-C of higher vertebrates was discovered.
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PMID:Natriuretic peptide receptors in the kidney and the ventral and dorsal aortae of the Atlantic hagfish Myxine glutinosa (Agnatha). 759 60

The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
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PMID:Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. 763 42

Autoradiography of frozen sections of fetal rat brain shows that receptor-like binding sites for atrial and C-type natriuretic peptides (ANP and CNP) occur in the generative juxtaventricular zone of the telencephalon after the 12th embryonic day (E12). These sites avidly bind both ANP and CNP. They thus resemble the cloned NPR-C type of natriuretic peptide receptor. Covalent cross-linking of 3-[125I]iodo-O-tyrosyl CNP-(1-22) and 3-[125I]iodo-28-tyrosyl rat ANP-(1-28) to membrane proteins from E16 telencephala labels a single protein band on reducing sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The protein has high affinities for ANP and CNP and a molecular mass of 60-70 kDa under reducing conditions, consistent with reduced NPR-C. However, because the telencephalic protein has unusual physicochemical properties in SDS under nonreducing conditions it was not possible to assess whether this protein can form disulfide-bridged dimers like NPR-C. CNP-(1-22) was a full agonist and ANP-(1-28) was a partial agonist of guanosine 3',5'-cyclic monophosphate (cGMP) production by E16 telencephalon. C-ANP, a synthetic ligand of NPR-C, antagonized CNP-(1-22)-mediated cGMP production. The results imply that either the NPR-C-like telencephalic receptor modulates the level of cGMP or a guanylate cyclase-coupled receptor, such as the 120-kDa B-type NPR, for which CNP-(1-22) is a full agonist, is present at levels insufficient to be detected by autoradiography or protein labeling.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Natriuretic peptide receptors are expressed during cerebral growth in the fetal rat. 765 46

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.
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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

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.
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PMID:The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer. 772 88

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.
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PMID:Cardiac distribution of the binding sites for natriuretic peptides in vertebrates. 774 80

In addition to atrial natriuretic peptide (ANP99-126) itself, linear peptide fragments from its N-terminal prohormone segment (pro-ANP) have been reported to have biological activity. In vivo, diuresis and natriuresis, as well as hypotension have been observed. In vitro, sodium uptake into medullary collecting duct cells was inhibited, and tone of vascular smooth muscle was reduced, associated with activation of guanylate cyclase. Such previous studies have used heterologous peptides and species, e.g., human pro-ANP1-30 or pro-ANP31-67, tested in rat, pig, or dog. The present experiments were designed to test whether rat pro-ANP1-30 or pro-ANP31-67 were natriuretic and hypotensive in rats, whether the two peptides showed specific binding to plasma membranes from rat kidney cortex or aorta, and whether they affected particulate guanylate cyclase activity in rat glomerular membranes. To extend in vitro results from the literature, the effect of human pro-ANP31-67 on transport in the rat medullary collecting duct in vivo was also tested. Although rat ANP99-126, as expected, increased diuresis and natriuresis, associated with inhibition of transport in the medullary collecting duct, in identically treated rats human pro-ANP31-67 was without effect. Similarly, only the ANP99-126 infusion resulted in reduction of arterial blood pressure. Furthermore, no diuretic, natriuretic, or hypotensive responses were observed in rats infused with either rat pro-ANP31-67 or pro-ANP1-30. In plasma membranes from rat kidney cortex or aorta, neither of the rat prosegments showed specific binding, or interference with ANP99-126 receptors. Finally, in contrast to ANP99-126, neither of the prosegments was able to increase basal guanylate cyclase activity in rat glomerular membranes. Therefore, under our experimental conditions we were unable to replicate the earlier results. This study thus does not support a regulatory role for pro-ANP fragments in blood volume or blood pressure homeostasis.
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PMID:Lack of biologic activity or specific binding of amino-terminal pro-ANP segments in the rat. 783

1. ANP (atrial natriuretic peptides)- or ANP/ATP-stimulated guanylyl cyclase activities were compared in adult (2 month old) and neonatal (5-7 day old) rat lung membrane fractions. 2. The enzyme activities of both membranes depended on the incubation time and ATP concentration: although the activities of both membranes were similar after a short incubation time (4 min), those in adult membranes were lower than those of neonatal membranes after longer incubation times (10 and 30 min) or at lower concentrations of ATP. 3. ANP/ATP gamma S-stimulated guanylyl cyclase activities, which were much higher than ANP/ATP-stimulated activities, were similar in both membranes. 4. ATPase activity of adult membranes was higher than that of neonatal membranes, suggesting that hydrolysis of ATP leads to a decrease of ANP/ATP-guanylyl cyclase activity in adult membranes. Triton X-100 enhanced and diminished ANP/ATP-stimulated guanylyl cyclase activities of adult and neonatal membranes, respectively, and thereby abolished the adult/neonatal difference in the membrane response to ATP. 5. ANP-stimulated activities of both membranes were much more activated by pre-incubation with ATP gamma S than those induced by simultaneous addition of ATP gamma S. The former activities were decreased to levels of the latter by Triton X-100. The latter activities were not affected by Triton X-100. 6. The present results suggested that conformation of lung plasma membranes is related to activation of the ANP receptor/guanylyl cyclase system.
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PMID:Developmental changes in ANP-stimulated guanylyl cyclase activity enhanced by ATP in rat lung membrane fractions. 783 9

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.
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PMID:Identification of renal natriuretic peptide receptor subpopulations by use of the non-peptide antagonist, HS-142-1. 785 88

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99-126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28,603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys' diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 mumol/kg intravenous of SQ 28,603 increased from 665 +/- 64 to 1015 +/- 224 mu Eq/3 h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 mumol/kg, p.o., of SQ 28,603 from 700 +/- 332 mu Eq/3 h in normal monkey to 2437 +/- 841 mu Eq/3 h. Therefore, the non-human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys treated with vehicle or 10 mumol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99-126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat. 4. SQ 28,603 and candoxatrilat (0.3 to 10 mumol/kg intravenous) each produced significant, dose-related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys receiving 5 mL/kg+0.2 mL/min saline. In addition, the highest dose of SQ 28,603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99-126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.
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PMID:Sodium loads enhance the natriuretic responses to atrial natriuretic peptide and neutral endopeptidase inhibitors in conscious cynomolgus monkeys. 788 75


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