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)

After the description in the past 5 years of BNP and CNP, interest in the natriuretic peptide family has dramatically increased. Molecular characterization of the receptors for this hormone family has identified a heterogeneity in the receptor subtypes not previously alluded to by pharmacological or biochemical studies. Much has been published on the physiology of ANP, but the major roles for BNP and CNP remain to be elucidated. Some experiments indicate that ANP and BNP may act synergistically, especially during cardiac stress; however, the high level of structural diversity of BNP among species and the ability of porcine BNP, but not human BNP, to activate human NPR-B suggest that an as yet unidentified receptor may exist that specifically recognizes BNP. Localization studies have implied that CNP is the most prominent neuropeptide in the natriuretic peptide family, and the restriction of its receptor, NPR-B, to the nervous system suggests that CNP and NPR-B may act in the brain to coordinate the central aspects of body fluid homeostasis. Of the three known NPRs, two, NPR-A and NPR-B, are capable of synthesizing their own second messenger, cGMP. The domain within these receptors that has high homology to protein kinases has been demonstrated to be essential for regulating this activity. No kinase activity has been measured in these proteins, but it is possible that this region is important for ATP regulation of guanylyl cyclase activity. This possibility raises interesting parallels with receptor-mediated cAMP signaling within cells. Seven transmembrane receptors, once activated by ligand, associate with G proteins to affect the activity of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of the natriuretic peptides and their receptors. 132 79

Preincubation of AtT-20 mouse pituitary tumour cells with the phorbol ester PMA resulted in a concentration-dependent inhibition of CNP-stimulated cyclic GMP production. The phorbol ester analogue 4 alpha phorbol had no inhibitory effect and 24 h preincubations with PMA resulted in a characteristic down-regulation of the response indicating that the inhibitory actions were mediated via the activation of protein kinase C. Forskolin in the presence of the phosphodiesterase inhibitor IBMX stimulated intracellular cyclic AMP concentrations by up to eight fold, but did not alter basal nor CNP-stimulated cyclic GMP production. These results indicate that CNP-stimulated guanylate cyclase activity associated with the GC-B natriuretic peptide receptor expressed in AtT-20 cells is inhibited by protein kinase C.
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PMID:Phorbol ester activation of protein kinase C inhibits CNP-stimulated cyclic GMP production in the mouse AtT-20 pituitary tumour cell line. 752 63

The production of cyclic GMP (cGMP) induced by acetylcholine and other stimuli was studied in bovine chromaffin cells. Acetylcholine increased intracellular cGMP in a transitory (peak at 2 min) and concentration-dependent manner (estimated half maximal increase, EC50 = 61 +/- 5 microM). NG-nitro-L-arginine methyl ester (NAME) inhibited such a rise in cGMP with a half maximal inhibitory concentration (IC50) of 231 +/- 55 microM. The acetylcholine-induced increase in cGMP was also inhibited by a calmodulin antagonist (calmidazolium, 30 microM) and by the absence of extracellular calcium. Other agents that strongly increased cytosolic calcium concentration ([Ca2+]i) as acetylcholine did, such as the nicotinic-agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP), high-KCl (50 mM), and ionomycin, also caused a rise in cGMP in cultured bovine chromaffin cells. Veratridine, an activator of sodium channels, produced a slowly developing calcium increase and no significant cGMP production. The muscarinic-agonist, muscarine, failed to increase cytosolic calcium, and was the weakest stimulator of cGMP production. cGMP formation, induced by sodium nitroprusside (SNP, 100 microM) and by C-type natriuretic peptide (CNP, 100 nM), was inhibited by 30-40% by increasing [Ca2+]i with ionomycin. This inhibition was abolished by calmidazolium (30 microM) and by the absence of calcium in the extracellular medium. In conclusion, bovine chromaffin cells synthesize nitric oxide (NO) to activate guanylate cyclase in response to several stimuli, which increase [Ca2+]i. Moreover, the increase in [Ca2+]i also stimulates a Ca2+/calmodulin phosphodiesterase, which could down-regulate the levels of cGMP in these cells.
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PMID:Activation of NO:cGMP pathway by acetylcholine in bovine chromaffin cells. Possible role of Ca2+ in the down-regulation of cGMP signaling. 757 35

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

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 natriuretic peptide (ANP) receptors were characterized in rat uterus. The binding of [125I]ANP to uterine membranes was completely competed for by increasing concentrations of unlabeled ANP (Kd = 0.39 nM) and brain natriuretic peptide (Kd = 1.24 nM) and partially by C-type natriuretic peptide (CNP; Kd = 80.4 nM), but not by C-ANF. Also, [125I]Tyr-CNP bound to uterine membranes was completely competed by unlabeled CNP (Kd = 1.12 nM). Cross-linking of [125I]ANP to uterine membranes revealed the presence of one band of 130 kilodaltons, corresponding to the guanylyl cyclase (GC-A and/or GC-B) subtypes of natriuretic peptide receptors. The presence of messenger RNA coding for genes of both GC-A and GC-B receptors was shown by quantitative reverse transcriptase polymerase chain reaction. Furthermore, ANP and, to a lesser degree, CNP stimulated the production of cGMP in rat uterus. Autoradiographic studies localized the highest binding of [125I]ANP in the endometrium, whereas [125I]Tyr-CNP binding was distributed in the endometrium as well as in the myometrium. These results demonstrate that rat uterine ANP receptors are of the guanylyl cyclase-coupled subtypes. The uterus is a target of natriuretic peptides where ANP induces its biological effects through the production of cGMP.
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PMID:Characterization and distribution of natriuretic peptide receptors in the rat uterus. 766 42

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

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

The ultracytochemical localization of particulate guanylate cyclase has been studied in lamb olfactory mucosa after activation with rat atrial natriuretic factor (rANF), porcine brain natriuretic peptide (pBNP), porcine C-type natriuretic peptide (pCNP) or rat brain natriuretic peptide (rBNP). Particulate guanylate cyclase is the receptor for these peptides and recently two subtypes of the cyclase have been identified. These isoforms are stimulated differently by ANF, BNP and CNP. Under our experimental conditions, rANF, pCNP and pBNP were strong activators of particulate guanylate cyclase in lamb olfactory mucosa, as demonstrated by the presence of reaction product. Samples incubated in basal conditions without rANF, pCNP or pBNP, or samples incubated in presence of rBNP did not reveal any cyclase activity. The rANF-stimulated cyclase activity was localized in the apical portion of olfactory epithelium. pCNP-stimulated guanylate cyclase was detected to the lamina propria in association with secretory cells of Bowman's glands and with cells in close relation with Bowman's glands (elongated cells and myoepithelial cells). The cyclase activity stimulated by pBNP was limited to cells of Bowman's glands. The present data indicate that ANF and CNP are recognized by different receptors and that BNP and CNP bind to the same receptor.
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PMID:Ultracytochemical localization of particulate guanylate cyclase after stimulation with natriuretic peptides in lamb olfactory mucosa. 788 88

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.
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PMID:Localisation and characteristics of natriuretic peptide receptors in the gills of the Atlantic hagfish Myxine glutinosa (Agnatha). 789 Oct 31


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