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 130 kDa atrial natriuretic factor receptor (ANF-R1) purified from bovine adrenal zona glomerulosa is phosphorylated in vitro by serine/threonine protein kinases such as cAMP-, cGMP-dependent and protein kinase C. This phosphorylation is independent of the presence of ANF (99-126) and there is no detectable intrinsic kinase activity associated with the ANF-R1 receptor or with its activated form. In bovine adrenal zona glomerulosa cells, TPA (phorbol ester) induces a marked inhibition of the ANF-stimulated cGMP accumulation as well as of the membrane ANF-sensitive guanylate cyclase catalytic activity without any change in the binding capacity or affinity for 125I-ANF. However, we have demonstrated a significant 32P incorporation in the ANF-R1 receptor of the TPA-treated cells. The effect of TPA on the zona glomerulosa ANF-R1 receptors was abolished by calphostin C, a specific protein kinase C inhibitor. Altered ANF actions due to blunted response of guanylate cyclase to ANF could be a consequence of the ANF receptor phosphorylation by excessive activity of protein kinase C and might be involved in the pathogenesis of hypertension.
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PMID:Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation. 128 Mar 21

The aim of this review is to provide a critical and concise discussion of present knowledge on the role of atrial natriuretic factor (ANF) in physiological as well as pathological pulmonary conditions. The lung contributes only to a small extent to the production of circulating ANF; on the other hand, the lung represents the major degrading site of the protein. Plasmatic ANF concentration increment during lung disease may therefore be due to a reduction in ANF plasma removal enzyme rather than to increased ANF production. Lung tissue shows more ANF receptor sites than any other organ. The effect of ANF on bronchial and pulmonary artery muscle lining is particularly evident. In fact ANF administration in asthmatic patients leads to bronchodilation comparable to dilation induced by salbutamol. Furthermore, elevated levels of circulating ANF seem to influence fluid redistribution through alveolar-capillary membrane leading to protein mobilization through the alveolar space. On the contrary, in the cardiomyopathic hamster ANF induces relevant guanylate cyclase activation before the animal has developed hemodynamic changes. Guanylate-cyclase activation may protect the lung through counteracting pulmonary edema formation, as shown by fluid reduction in alveolar spaces following pneumotoxic agents administration. This effect seems independent of natriuretic and hypotensive ANF effects.
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PMID:[Atrial natriuretic factor and pulmonary function]. 129 35

Hepatocytes are known to synthesize nitric oxide (NO) from L-arginine via an inducible NO synthase. Studies were performed to determine the relationship between hepatocyte NO production and the stimulation of hepatocyte soluble guanylate cyclase. A combination of lipopolysaccharide (LPS), interferon-gamma, tumor necrosis factor, and interleukin-1 stimulates the biosynthesis of large quantities of nitrite and nitrate (NO2- + NO3-). Hepatocyte NO2- + NO3- production was associated with only small increases in intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels but much greater increases in extracellular cGMP release over an 18-h time period. This cGMP synthesis was dependent on the L-arginine concentration and was inhibited in a reversible manner by NG-monomethyl-L-arginine. The cytokines or LPS added alone induced small increases in nitrogen oxide production and concomitant minor elevations in cGMP release. Atrial natriuretic peptide also stimulated the release of cGMP by hepatocytes which appeared to be independent of the cytokine+LPS-induced cGMP release. The addition of probenecid reduced the cGMP release by 66%, while cell damage was excluded as a cause for the extracellular release. Addition of 3-isobutyl-1-methylxanthine, but not M&B 22948, increased hepatocyte intra- and extracellular cGMP levels after cytokine+LPS stimulation. Induction of nitrogen oxide synthesis by hepatocytes in vivo by injecting rats with killed Corynebacterium parvum resulted in increased cGMP levels in freshly isolated hepatocytes and increased cGMP release by the hepatocytes when placed in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Association between synthesis and release of cGMP and nitric oxide biosynthesis by hepatocytes. 131 86

The original observation by de Bold et al. (1981) of a rapid, massive, and short-lasting diuretic and natriuretic effect following injection of rat atrial extracts into intact rats, led to the identification, isolation and purification of the atrial natriuretic factor (ANF). ANF is stored in atrial myocytes and released into the blood stream by atrial distension. Available data suggest that the mechanism of ANF-induced natriuresis involves either renal hemodynamic effects, such as the increase in glomerular filtration rate and reduction of medullary tonicity, or direct effect on sodium transport in the medullary collecting ducts. ANF induces relaxation of vascular smooth muscle, decreases blood pressure and cardiac output. All these effects displayed by ANF are associated to the an inhibition of aldosterone, renin and vasopressin release. Most of these actions are mediated by specific high affinity receptors, which are coupled to a particulate guanylate cyclase. Although ANF levels are increased in some disorders, such as severe heart failure, hypertension, chronic renal failure, the role of the peptide is uncertain. To better define the potential physiopathological role and the possible therapeutic implications of this new hormonal system in conditions of disturbed body fluid and sodium homeostasis, further experimental and clinical data must be awaited.
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PMID:[The physiopathological aspects of the atrial natriuretic factor]. 131 27

We have compared the levels and subtypes of atrial natriuretic peptide (ANP) receptors in astrocyte glial and neuronal cultures prepared from the hypothalamus and brain stem of 1-day-old rats. Astrocyte glial cultures contain approximately twice the number of ANP receptors, as measured by 125I-ANP specific binding, compared with neuronal cultures. Rat ANP-(99-126), rat brain natriuretic peptide (BNP32), C-type natriuretic peptide (CNP-22), atriopeptin I, and [des-Gln18,Ser19,Gly20,Leu21, Gly22]atrial natriuretic factor-(4-23)-NH2[C-ANF-(4-23)] all competed strongly for 125I-ANP binding in both culture types, with inhibitory constant values ranging from 0.47 to 8.07 nM. The presence of ANP-C receptors (clearance type) in both cell types is indicated from the strong competition of 125I-ANP specific binding by C-ANF-(4-23). The potency profiles for stimulation of guanosine 3',5'-cyclic monophosphate levels by these peptides were ANP = BNP much greater than CNP-22 greater than atriopeptin I in astrocyte glia and CNP-22 much greater than BNP32 greater than ANP greater than atriopeptin I in neuronal cultures. These results indicate that both types of culture contain guanylate cyclase-coupled ANP receptors, with astrocytes containing predominantly the ANP-A subtype and neurons predominantly the ANP-B subtype.
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PMID:Atrial natriuretic peptide receptor subtypes in rat neuronal and astrocyte glial cultures. 131 98

Mesangial cells possess a variety of receptors for hormones and autacoids. They are also equipped with ectoenzymes whose function may be to control the availability of autacoids and hormones at their receptor sites. Several examples are considered. Receptors for angiotensin II (AII) are present both on murine and human mesangial cells. One single group of receptors has been demonstrated in each of these preparations. Mesangial cell AII receptors are linked to phospholipase C via a G protein. They belong to the AT1 subtype because (125I)AII is displaced from its binding sites preferentially by AT1 antagonists such as DUP 753 and EXP 3,174, whereas AT2 antagonists are much less potent. AT1 antagonists suppress the biological effects of AII in mesangial cells, including the stimulation of intracellular calcium concentration and the increase of prostaglandin synthesis and of (3H)leucine incorporation. Mesangial cells also have receptors for atrial natriuretic factor, but the distribution between B receptors with guanylate cyclase activity and clearance (C) receptors varies with the species. Both types are present in murine mesangial cells, whereas only C receptors are found in human mesangial cells. In contrast, human epithelial cells possess both B and C receptors. Ecto-5'-nucleotidase activity results in the production of adenosine, which acts on mesangial cells through A1 and A2 receptors. This enzyme is markedly induced in rat mesangial cells by interleukin-1, whose effect is mediated in part by prostaglandin E2 and cAMP. Various other cAMP-stimulating agents also induce 5'-nucleotidase expression in rat mesangial cells. Ectopeptidases are present in all glomerular cell types but essentially in epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell surface receptors and ectoenzymes in mesangial cells. 131 10

One of the atrial natriuretic factor (ANF) receptors is a 180 kDa protein (180 kDa mGC) which possesses the extraordinary characteristic of being bifunctional: it is both a receptor and a guanylate cyclase. In addition to the 180 kDa mGC, there exists another 120-130 kDa protein which is also bifunctional and a 120 kDa disulfide-linked dimeric cell surface protein that is an ANF receptor, but is not a part of guanylate cyclase. A fundamental question that needs to be resolved is: Are these three apparently biochemically distinct ANF receptors structurally similar? With the aid of affinity crosslinking techniques, a highly specific antibody to the 180 kDa mGC, and GTP-affinity techniques, we now demonstrate the presence of three immunologically similar proteins in rat adrenal gland and testes. These proteins migrate as 180 kDa, 130 kDa and 65 kDa under denaturing sodium dodecyl sulfate polyacrylamide gel electrophoresis and specifically bind ANF, raising one or more of the following possibilities about their relationships: 1) Degradation of 180 kDa to 130 kDa and 65 kDa occurs during purification; 2) 180 kDa bears a precursor-product relationship with 130 kDa and 65 kDa, suggesting the role of a protease in the processing procedure; 3) these proteins are a result of gene splicing; or 4) they are the products of three separate, but very closely related genes.
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PMID:Three immunologically similar atrial natriuretic factor receptors. 131 50

Atrial natriuretic peptide (ANP) has been shown to affect water and ion transport and specific ANP binding has been identified in several secretory tissues. ANP commonly acts via stimulation of membrane-bound particulate guanylate cyclase with the production of cyclic guanosine monophosphate (cGMP). We questioned whether ANP played a role in the complex cyclic transformation of the endometrium into a secretory tissue, and whether its action was cGMP mediated. Endometrium was obtained by biopsy in regularly menstruating women and stromal cells were isolated and cultured for use in this study. ANP competitive binding assays were performed using 125I-labeled ANP (0.1 nmol/L) and increasing concentrations of unlabeled ANP (0-1000 nmol/L). Optimal binding was obtained after 3-h incubation at 4 C and binding characteristics, including dissociation constant and binding site quantity, were estimated by Scatchard analysis. Specific, high affinity (dissociation constant, 0.078 +/- 0.004 nmol/L) and low capacity (4,877 +/- 1,951 binding sites/cell) ANP binding was identified, with nonspecific binding representing less than or equal to 16% of total binding. Evaluation of ANP-stimulated cyclic nucleotide production revealed an increase in cGMP production, with a 7-fold increase at 1000 nmol/L ANP, and no effect on cAMP production. In conclusion, we have identified specific high affinity receptors for ANP in human endometrial cells, suggesting a role for ANP in endometrial cell function and/or development mediated via cGMP production. We propose that ANP may affect local salt and water metabolism, may be involved in the secretory evolution of glandular and stromal cells, and may further facilitate endometrial development via modulation of local vascular tone and endothelial permeability.
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PMID:Atrial natriuretic peptide receptors in human endometrial stromal cells. 132 28

Atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are vasoactive peptides produced in cells of the cardiovascular system. We examined the effects of ANP on ET-1 transcription, production (translation), and secretion in cultured bovine aortic endothelial cells (BAEC). ANP and C-ANP 4-23 (a specific ligand for the C or non-guanylate cyclase receptor) equipotently inhibited the synthesis of prepro-ET-1 and ET-1 proteins in BAEC by at least 50%. Both of these forms of ANP and another C receptor specific ligand, nanopiperazine ANP (11-15)-NH2, inhibited ET-1 secretion by as much as 55%. LY 83583, an inhibitor of ANP-induced cGMP generation, failed to reverse the ANP-induced inhibition of ET-1 secretion. This further indicated that the guanylate cyclase-linked B receptor is not involved. The decreased ET-1 secretion caused by C-ANP 4-23 was reversed by 8-bromo-cAMP or amiloride, which prevents ANP-induced inhibition of cAMP. We also found that ANP and C-ANP 4-23 augmented ET-1 mRNA levels in BAEC by prolonging the mRNA half-life. ANP or cycloheximide comparably inhibited ET-1 translation while increasing ET-1 mRNA levels, suggesting that the two events are related. These results indicate that ANP inhibits ET-1 protein production and secretion while stabilizing the ET-1 mRNA. The effects of ANP are mediated through the C receptor and are probably the result of ANP inhibiting the generation of cAMP. These findings suggest a potentially important new function for this receptor to mediate, in part, the interactions of ANP and ET in the vasculature.
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PMID:Atrial natriuretic peptide inhibits the production and secretion of endothelin from cultured endothelial cells. Mediation through the C receptor. 132 35

1. The mechanical and biochemical effects of agents that relax vascular smooth muscle either through elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) or adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were compared in isolated ring preparations of human umbilical artery and rat aorta. Tone was established by preconstriction with 5-hydroxytryptamine. 2. The endothelium-dependent vasodilator calcium ionophore (A23187) (which stimulates endothelium-derived relaxing factor [EDRF] release and thus acts through soluble guanylyl cyclase), sodium nitroprusside (which stimulates soluble guanylyl cyclase directly), and atrial natriuretic peptide (which stimulates particulate guanylyl cyclase) relaxed rat aorta but not human umbilical artery. 3. Sodium nitroprusside, 10 microM, increased cyclic GMP levels from 10 to 390 pmol mg-1 protein at 2 min in rat aorta, as compared with a slower, relatively attenuated rise from 5 to 116 pmol mg-1 protein after 15 min in human umbilical artery. The rise in cyclic GMP in the umbilical artery was not significantly augmented by the cyclic GMP phosphodiesterase inhibitor, MB22948. Atrial natriuretic peptide increased cyclic GMP levels in rat aorta but not in human umbilical artery. 4. Forskolin, 10 microM, which stimulates both soluble and particulate adenylyl cyclase, maximally relaxed rat aorta and increased cyclic AMP levels from 15 to 379 pmol mg-1 protein at 15 min, but did not significantly relax or increase cyclic AMP levels in human umbilical artery. After preincubation with the cyclic nucleotide phosphodiesterase inhibitor, IBMX, 10 microM forskolin increased cyclic AMP levels to 1365 pmol mg-1 protein at 30 min in human umbilical arteries, but these high levels were not accompanied by mechanical relaxation.5. 8-Bromo-cyclic GMP and 8-bromo-cyclic AMP which are lipophilic analogues of cyclic GMP and cyclic AMP, both maximally relaxed the rat aorta at a concentration of 10 microM, but did not significantly relax the human umbilical artery.6. The findings indicate that elevated cyclic nucleotide levels are not associated with mechanical relaxation of the post-partum human umbilical artery, as in other vessels such as rat aorta. This impaired response to cyclic nucleotides may contribute to closure of the umbilical artery after birth.
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PMID:Impaired cyclic nucleotide-mediated vasorelaxation may contribute to closure of the human umbilical artery after birth. 132 77


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