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 endocrine function of the heart is to secrete Atrial and Brain natriuretic -peptides (ANP and BNP). These peptides are biologically active via particulate guanylate cyclases which generate cyclic GMP, the second intracellular messenger. A polysaccharide antagonist, HS-142-1 has been recently described by a Japanese Group. Cyclic GMP is partly secreted from the target cells into the extra cellular medium in which its accumulation is proportional to the concentration of the natriuretic peptide. Neutral Endopeptidase (NEP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides. NEP is absent in plasma but present on the surface of endothelial and smooth muscle cells. NEP is mainly expressed at the apical pole of the epithelial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is associated with the oversecretion of natriuretic peptides. This chronic phenomenon involves the recruitment of all the cardiac myocytes to express natriuretic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic peptides correlate with the level of the -hemodynamic stress. Therefore the plasma levels of natriuretic peptides are good pronostic markers in both experimental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also -correlated with the plasma and urinary levels of cyclic GMP. The plasma level of -cyclic GMP is correlated with the endothelial concentration of cyclic GMP but not with the cyclic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells and is related to particulate guanylate cyclase activity. In contrast natriuretic peptides do not modulate vascular wall cyclic GMP content. The natriuretic action of ANP is probably due to the interaction of the filtered peptide with the particulate guanylate cyclase at the apical pole of the epithelial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urinary compartment. It is also by a urinary pathway via the macula densa that ANP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP correlate with the degree of salt retention in congestive heart failure, provides evidence for chronic desensitization of the system. An up-regulation of Na(+), K(+), 2Cl(-) expression associated with experimental congestive heart failure has recently been shown. Similarly, a modulation of the different sodium transporter systems along the nephron could be one of the counter-regulations leading to desensitization to natriuretic peptides. In conclusion, natriuretic peptides are true endocrine peptides, secreted by the heart, transported in the plasma, filtered by the glomeruli and active at the nephron level. The molecular effector of ANP and cyclic GMP in the epithelial cells is probably the G-kinase II, isoform phosphorylating the cystic fibrosis transmembrane conductance regulator (CFTR). The exact mechanism of desensitization remains to be elucidated.
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PMID:[Functional compartmentation of the endocrine action of cardiac natriuretic peptides]. 1079 May 90

In the vertebrate retina, cyclic guanosine monophosphate (cGMP) mediates photoreceptor signal transduction and modulates ion channel and gap junction conductivity. Although most previous studies have focused on its synthesis by nitric oxide (NO)-sensitive soluble guanylate cyclase, cGMP is also synthesized by NO-insensitive particulate guanylate cyclases (pGC). Natriuretic peptides and their associated pGC-coupled receptors have been reported in retina, but few studies have localized these natriuretic peptides or pGCs to specific retinal cells or demonstrated that activation of pGCs by natriuretic peptides increases cGMP synthesis. In this study, we immunocytochemically localized atrial, brain, and C-type natriuretic peptide-like immunoreactivity (ANP-LI, BNP-LI, and CNP-LI, respectively) in turtle retina by using isoform specific antisera, and determined the ability of each natriuretic peptide isoform to increase cGMP-like immunoreactivity (cGMP-LI) in retinal cells. ANP-LI and CNP-LI were localized in sparsely distributed amacrine cells with thin, intermittently varicose processes in the inner plexiform layer. BNP-LI was localized to abundant somata in the inner nuclear and ganglion cell layers and in specific amacrine and horizontal cells. Stimulation of turtle eyecups with each of these natriuretic peptides increased cGMP-LI in multistratified amacrine cells by means of NO-independent mechanisms in the central retina, and in select amacrine and bipolar cells in the peripheral retina by a nitric oxide-dependent mechanism. These results indicate that natriuretic peptides can modulate the synthesis of cGMP in select retinal neurons by two distinct signal transduction pathways in a regionally specific manner.
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PMID:Localization of natriuretic peptides and their activation of particulate guanylate cyclase and nitric oxide synthase in the retina. 1093 90

Natriuretic peptide binding sites were examined in the gills of the hagfish Eptatretus cirrhatus (Class Agnatha, subfamily Eptatretinae) using radio-ligand binding techniques, molecular cloning and guanylyl cyclase assays. Iodinated rat atrial natriuretic peptide ((125)I-rANP) and iodinated porcine C-type natriuretic peptide ((125)I-pCNP) bound specifically to the lamellar folds and cavernous tissue of E. cirrhatus gills, and 0.3 nmol l(-1) rat ANP competed for 50 % of specific (125)I-rANP binding sites. Affinity cross-linking of (125)I-rANP to gill membranes followed by sodium dodecylsulphate-polyacrylamide gel electrophoresis revealed a single binding site of 150 kDa. In the presence of Mn(2+), 0.1 nmol l(-1) rANP inhibited cGMP production, whereas 1 micromol l(-1) rANP stimulated cGMP production rates. At 1 micromol l(-1), pCNP also stimulated cGMP production. The production of cGMP was also measured in the presence and absence of ATP with either Mn(2+) or Mg(2+). Reverse transcriptase polymerase chain reaction (RT-PCR) of hagfish gill RNA, followed by cloning and sequencing of PCR products, produced a partial cDNA sequence of a natriuretic peptide guanylyl cyclase receptor. The deduced amino acid sequence indicated 87-91 % homology with other natriuretic peptide guanylyl cyclase receptors. This study indicates the presence of a natriuretic peptide guanylyl cyclase receptor in the gills of E. cirrhatus that is similar to the natriuretic peptide guanylyl cyclase receptors in higher vertebrates. These observations demonstrate that the coupling of natriuretic peptide receptors with guanylyl cyclase has a long evolutionary history.
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PMID:Evidence of a guanylyl cyclase natriuretic peptide receptor in the gills of the new zealand hagfish Eptatretus cirrhatus (Class Agnatha). 1093 96

ANP and NO act via different receptors, although inducing the common intracellular messenger - cyclic GMP. However, interaction between both factors remains unclear. Our observations suggested that in the rat kidney glomeruli, activities of the ANP- and NO-dependent guanylyl cyclase systems may be mutually compensated. To check this, we have tested effects of ANP and sodium nitroprusside (SNP) on cGMP synthesis and relaxation of glomeruli contracted with angiotensin II. The glomeruli were isolated from Wistar rats receiving saline (Control), dexamethasone (DEX), deoxycorticosterone (DOCA) or N-c-nitro-L-arginine methyl ester (NAME) for 1 or 2 days. In the DEX glomeruli exposed to 100 microM SNP, rate of cGMP synthesis was significantly higher then in the Control (26.3 vs 16.0 pmol/mg.prot./2 min., P<0.05), while 1 microM ANP was markedly less effective (2.8 vs 16.7 pmol/mg.prot./2 min in Control, P<0.01). On the contrary, in NAME group 1 microM ANP stimulated cGMP synthesis up to 35.6 pmol/mg.prot./2 min whereas efficacy of SNP was slightly suppressed. High correlation coefficient (r = 0.979, p<0.01) indicates interrelationship between NO- and ANP-dependent cGMP synthesis. Ability of the glomeruli to relax in response to ANP or SNP was in accord to their ability to cGMP generation. This was confirmed by high correlation (r = 0.845, p<0.001) between degree of relaxation and rate of cGMP synthesis. Our results support strongly the hypothesis that both, ANP and NO dependent systems co-operate in regulation of the function of kidney glomeruli.
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PMID:Co-operation between particulate and soluble guanylyl cyclase systems in the rat renal glomeruli. 1101 69

Natriuretic peptide receptors in the central vasculature of the toad, Bufo marinus, were characterized using autoradiographical, molecular, and physiological techniques. Specific 125I-rat ANP binding sites were present in the carotid and pulmonary arteries, the lateral aorta, the pre- and post-cava, and the jugular vein, and generally occurred in each layer of the blood vessel. The 125I-rat ANP binding was partially displaced by the specific natriuretic peptide receptor C ligand, C-ANF, which indicates the presence of two types of natriuretic peptide receptors in the blood vessels. This was confirmed by a RT-PCR study, which demonstrated that guanylyl cyclase receptor (NPR-GC) and NPR-C mRNAs are expressed in arteries and veins. An in vitro guanylyl cyclase assay showed that frog ANP stimulated the production of cGMP in arterial membrane fractions. Physiological recordings from isolated segments of the carotid and pulmonary arteries and the lateral aorta, which had been pre-constricted with arginine vasotocin, showed that rat ANP, frog ANP and porcine CNP relaxed the vascular smooth muscle with relatively similar potency. Together, the data show that the central vasculature contains two types of natriuretic peptide receptors (NPR-C and NPR-GC) and that the vasculature is a target for ANP and CNP.
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PMID:Natriuretic peptide receptors in the central vasculature of the toad, Bufo marinus. 1122 87

Natriuretic peptides (NPs) and their receptors have been identified in vertebrate species ranging from elasmobranchs to mammals. Atrial, brain and ventricular NP (ANP, BNP and VNP) are endocrine hormones secreted from the heart, while C-type NP (CNP) is principally a paracrine factor in the brain and periphery. In elasmobranchs, only CNP is present in the heart and brain and it functions as a circulating hormone as well as a paracrine factor. Four types of NP receptors are cloned in vertebrates. NPR-A and NPR-B are guanylyl cyclase-coupled receptors, whereas NPR-C and NPR-D have only a short cytoplasmic domain. NPs are hormones important for volume regulation in mammals, while they act more specifically for Na(+) regulation in fishes. The presence of NP and its receptor has also been suggested in the most primitive vertebrate group, cyclostomes, and its molecular identification is in progress. The presence of ANP or its mRNA has been reported in the hearts and ganglia of various invertebrate species such as mollusks and arthropods using either antisera raised against mammalian ANP or rat ANP cDNA as probes. Immunoreactive ANP has also been detected in the unicellular Paramecium and in various species of plants including Metasequoia. Furthermore, the N-terminal prosegments of ANP, whose sequences are scarcely conserved even in vertebrates, have also been detected by the radioimmunoassay for human ANP prosegments in all invertebrate and plant species examined including Paramecium. Although these data are highly attractive, the current evidence is too circumstantial to be convincing that the immunoreactivity truly originates from ANP and its prosegments in such diverse organisms. The caution that has to be exercised in identification of vertebrate hormones from phylogenetically distant organisms is discussed.
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PMID:Does the natriuretic peptide system exist throughout the animal and plant kingdom? 1139 92

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC(50) values 2.98 nM (95% CI: 1.49 - 5.95 nM and 8.58 (4.72 - 15.6 nM) respectively)). The NO-donor diethylamine NONOate fully reversed the ET-1 constriction in conductance CA (E(MAX) 127+/-9.16%), however only partial reversal was observed in resistance CA (E(MAX) 78.8+/-8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 microM) reduced the maximum response to diethylamine NONOate to 76.9+/-14.4% in conductance CA (P<0.05), but had no effect on resistance CA (E(MAX) 77.2+/-18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC(50) values 4.25 nM (0.84 - 21.4 nM) and 18.4 nM (2.92 - 116 nM), E(MAX) 53.1+/-14.7% and 48.6+/-11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC(50) value was 2.4 nM (0.74 - 7.75 nM), E(MAX) 54.5+/-14.9%. Concentration-response curves to BNP were incomplete in resistance CA. Concentration-response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET-1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET-1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.
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PMID:Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery. 1139 74

The intestinal peptides, guanylin and uroguanylin, may have an important role in the endocrine control of renal function. Both peptides and their receptor, guanylyl cyclase C (GC-C), are also expressed within the kidney, suggesting that they may act locally in an autocrine/paracrine fashion. However, their physiological regulation within the kidney has not been studied. To begin to address this issue, we evaluated the distribution of uroguanylin and guanylin messenger RNA (mRNA) in the mouse nephron and the regulation of renal expression by changes in dietary salt/water intake. Expression was determined in 1) wild-type mice, 2) two strains of receptor-guanylyl cyclase-deficient mice (ANP-receptor-deficient, GC-A-/-, and GC-C-deficient mice); and 3) cultured renal epithelial (M-1) cells, by RT-PCR, Northern blotting and immunocytochemistry. Renal uroguanylin messenger RNA expression was higher than guanylin and had a different distribution pattern, with highest levels in the proximal tubules, whereas guanylin was mainly expressed in the collecting ducts. Uroguanylin expression was significantly lower in GC-C-/- mice than in GC-A-/- and wild-types, suggesting that absence of a receptor was able to down-regulate ligand expression. Salt-loading (1% NaCl in drinking water) increased uroguanylin-mRNA expression by >1.8-fold but had no effect on guanylin expression. Uroguanylin but not guanylin transcripts were detected in M-1 cells and increased in response to hypertonic media (+NaCl or mannitol). Our results indicate that high-salt intake increases uroguanylin but not guanylin expression in the mouse kidney. The synthesis of these peptides by tubular epithelium may contribute to the local control of renal function and its adaptation to dietary salt.
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PMID:High salt intake increases uroguanylin expression in mouse kidney. 1141 31

Muscarinic activation of bovine tracheal smooth muscle (BTSM) is involved in cyclic guanosine monophosphate (cGMP) production mediated through soluble (sGC) and membrane-bound (mGC) guanylyl cyclases. A muscarinic- and NaCl-sensitive mGC exists in BTSM regulated by muscarinic receptors coupled to G proteins. To identify the mGCs expressed in BTSM, reverse transcriptase/polymerase chain reaction (RT-PCR) from total RNA was performed using degenerate oligonucleotides for amplification of a region conserved among GC catalytic domains. Cloning of amplification products revealed that 76% of all BTSM GC transcripts corresponded to the sGC beta1 subunit and 24% to the B-type (C-type NP 1-22 [CNP]-sensitive) GC receptor. cGMP production by BTSM membrane and soluble fractions confirmed that sGC activity is 3-fold with respect to mGC activity. RT-PCR using specific oligonucleotides revealed that A (atrial NP-sensitive) and C (guanylin-sensitive) mGC subtypes are also expressed in BTSM. Stimulation of basal plasma membrane GC activity by CNP was higher than that by ANP, whereas guanylin showed no effect, indicating that CNP-sensitive guanylyl cyclase (GC-B) is the predominant functional BTSM mGC subtype. Strong adenosine triphosphate inhibition of CNP-stimulated mGC activity supports the finding that the tracheal mGC isoform belongs to the natriuretic peptide-sensitive mGCs. Additionally, CNP was able to reverse the chloride inhibition of BTSM mGC activity, suggesting that this is a novel G protein-coupled GC-B receptor.
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PMID:Molecular and biochemical characterization of a CNP-sensitive guanylyl cyclase in bovine tracheal smooth muscle. 1147 81

Effects of actual and simulated weightlessness on choroidal guanylate cyclase activity were evaluated by assaying the production of cyclic guanosine monophosphate (cGMP), a second messenger involved in mechanisms regulating the secretion of cerebrospinal fluid (CSF) in choroid plexus. Cyclic cGMP was measured, using radio-immunoassay, in choroidal extracts of hindlimb-suspended rats (HLS rats), adapted to an anti-orthostatic restraint for 30 min., or for 3, 9 or 14 days and after a 17-day spaceflight (Life and Microgravity SpaceLab experiment; LMS). Basal cGMP levels were slightly but significantly decreased in the first 30 min. of the HLS experiment, whereas they were significantly increased in rats adapted to longer anti-orthostatic restraints. LMS flight rats demonstrated a similar increase in the choroidal cGMP baseline. After natriuretic peptide stimulation, i.e. using ANP (atrial natriuretic peptide) or BNP (brain natriuretic peptide), choroidal cGMP contents were typically increased (by 1.5-2 times; p<0.05) in control rats (LMS and HLS experiments), but not significantly elevated in suspended rats, except for those adapted to HLS for 14 days. In these animals the ANP-dependent cGMP production was significantly increased (by about 3 times; p<0.005). The ANP- or BNP-dependent responses were similarly abolished in LMS flight rats, which were dissected 4-6 hours after return to Earth's gravity. The role of corticosteroids was also investigated during the LMS experiment. Results on choroidal functions revealed a lack of significant change of cGMP levels between adrenalectomized and sham-operated rats. For the first time, it is reported that both basal and ANP- stimulated cGMP levels are dramatically changed over the first 14 days of suspension, i.e. with experiments known to simulate some effects of weightlessness. Basal choroidal cGMP levels are also increased after 17 days in space, suggesting that space adaptation also impacts choroidal guanylate cyclase activities. However, the absence of ANP-dependent cGMP increase, observed in LMS flight animals, suggests that HLS could not simulate all the spaceflight effects. Thus, these preliminary results seem to show that a natriuretic peptides-independent s stem is involved in choroidal adaptation to spaceflight.
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PMID:Hindlimb-suspension and spaceflight both alter cGMP levels in rat choroid plexus. 1154 82


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