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 main objective of this study was to find out if the reported changes in the aldosterone-suppressant activity of atrial natriuretic peptide (ANP) during different hormonal states in rats are due to a modulation of ANP receptors. In zona glomerulosa cells, ribonuclease protection assay detected mRNAs for guanylate cyclase (GC)-coupled ANP GC-A and GC-B receptors, and for ANP C receptors, which are not coupled to GC. Western analysis using polyclonal anti-GC-A and anti-GC-B receptor antibodies revealed the presence of GC-A but not GC-B receptor proteins in zona glomerulosa cells. Pregnancy (days 7, 16 and 21), oestradiol-17 beta and progesterone decreased mRNAs for all the three ANP receptors in zona glomerulosa cells. Pregnancy decreased GC-A receptor proteins in zona glomerulosa cells, but these recovered to virgin values on day 2 postpartum. ANP receptor mRNAs in zona glomerulosa cells increased by postpartum day 2, but did not reach the values found in virgin rats. Zona fasciculata mainly contained GC-A receptor mRNA. It is concluded that ANP receptors in rat adrenal zona glomerulosa are modulated by pregnancy, oestrogen and progesterone; a decrease in ANP GC-A receptors during pregnancy might explain the accompanying decrease in the aldosterone-suppressant effects of ANP.
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PMID:Downregulation of adrenal atrial natriuretic peptide receptor mRNAs and proteins by pregnancy in rats. 948 97

The natriuretic peptide family consists of three structurally related endogenous ligands: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The biological actions of natriuretic peptides are thought to be mediated through the activation of two guanylyl cyclase (GC)-coupled receptor subtypes (GC-A and GC-B). In this study, we examined the effects of ANP and CNP, which are endogenous ligands for GC-A and GC-B, respectively, on bone growth using an organ culture of fetal mouse tibias, an in vitro model of endochondral ossification. CNP increased the cGMP production much more potently than ANP, thereby resulting in an increase in the total longitudinal bone length. Histological examination revealed an increase in the height of the proliferative and hypertrophic chondrocyte zones in fetal mouse tibias treated with CNP. The natriuretic peptide stimulation of bone growth, which was mimicked by 8-bromo-cGMP, was inhibited by HS-142-1, a non-peptide GC-coupled natriuretic peptide receptor antagonist. The spontaneous increase in the total longitudinal bone growth and cGMP production was also inhibited significantly by HS-142-1. CNP mRNA was expressed abundantly in fetal mouse tibias, where no significant amounts of ANP and BNP mRNAs were detected. A considerable amount of GC-B mRNA was present in fetal mouse tibias. This study suggests the physiologic significance of the CNP/GC-B pathway in the process of endochondral ossification.
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PMID:Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. 956 90

C-type natriuretic peptide (CNP) is a newly discovered factor that stimulates vasorelaxation and inhibits cell proliferation. Natriuretic peptide receptor-B (NPR-B) is the primary signaling molecule for CNP. Recently, the guanylyl cyclase activity of NPR-B was shown to correlate with its phosphorylation state, and it was suggested that receptor dephosphorylation is a mechanism of desensitization. We now report the identification and characterization of the major NPR-B phosphorylation sites. Mutagenesis and comigration studies using synthetic phosphopeptides were employed to identify five residues (Ser-513, Thr-516, Ser-518, Ser-523, and Ser-526) within the kinase homology domain that are phosphorylated when NPR-B is expressed in human 293 cells. Mutation of any of these residues to alanine reduced the receptor's phosphorylation state and CNP-dependent guanylyl cyclase activity. The reductions were not explained by decreases in receptor protein level as indicated by immunoblot analysis and determinations of cyclase activity in the absence of CNP or in the presence of detergent. Elimination of all of the phosphorylation sites resulted in a completely dephosphorylated receptor whose CNP-dependent cyclase activity was decreased by >90%. However, unlike NPR-A, the dephosphorylated receptor was not completely unresponsive to hormone. Finally, two additional residues (Gly-521 and Ser-522) were identified that when mutated to alanine reduced the overall phosphorylation state and hormone responsiveness of the receptor without abolishing the phosphorylation of a specific site. These data indicate that phosphorylation of the kinase homology domain is a critical event in the regulation of NPR-B.
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PMID:Identification and characterization of the major phosphorylation sites of the B-type natriuretic peptide receptor. 962 42

The effect of isatin on rat brain particulate guanylate cyclase (GC) was investigated. The enzyme was stimulated by atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and urodilatin, but not by C-type natriuretic peptide (CNP). Their effects were not additive, pointing to action via the GC-A receptor. Isatin, in dose-dependent manner, abolished this stimulation. The non-hydrolysable ATP analogue, adenylylimidodiphosphate, potentiated the effects of submaximal doses of ANP, BNP and urodilatin on this particulate GC-A, and attenuated or abolished sensitivity to isatin. These results suggest that isatin antagonises the generation of second messenger by GC-A; this sensitivity might be regulated at an ATP binding site, possibly a protein kinase-like domain.
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PMID:Interaction of isatin with type-A natriuretic peptide receptor: possible mechanism. 965 Nov 5

Atrial natriuretic peptide (ANP) receptors were characterized in rat oral mucosa using quantitative in vitro autoradiography and activation of particulate guanylyl cyclase (GC) by natriuretic peptides. Competition-binding analysis performed by quantitative in vitro autoradiography demonstrated specific [125I]rANP(1-28) binding sites in the tongue and hard palate. The precise location of this binding was revealed on the basal and parabasal cells of the epithelia by microautoradiography. The dissociation constant (Kd) and maximal binding capacity (Bmax) of these sites were 3.34+/-1.35 nM and 2.71+/-2.21 fmol/mm2 on the epithelium of the tongue, and 4.09+/-1.52 nM and 3.45+/-3.01 fmol/mm2 on the epithelium of the hard palate, respectively. Receptor subtypes were characterized by competition with des [Gln18, Ser19, Gly20, Leu21, Gly22] ANP(4-23) (C-ANP), a specific ligand for the clearance receptor (NPR-C). These binding sites were displaced by C-ANP with inhibition constant (Ki) of 8.96+/-3.18 nM and Bmax of 2.89+/-2.45 fmol/mm2 on the epithelium of the tongue, and Ki of 9.12+/-2.71 nM and Bmax of 3.08+/-2.94 fmol/mm2 on the epithelium of the hard palate, respectively. Production of cyclic GMP by particulate GC in the epithelial membranes of the tongue and hard palate was stimulated by rANP(1-28), porcine brain natriuretic peptide (BNP)(1-26), and C-type natriuretic peptide (CNP)(1-22) in a dose-dependent manner. These results indicate that ANP-binding sites in the epithelium of the tongue and hard palate are mainly clearance receptors (NPR-C) but biological receptors (NPR-A and/or NPR-B) with GC activity are also present, and suggest that ANP may have a role in the proliferation of the oral epithelial cells, especially in the tongue and hard palate.
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PMID:Localization of atrial natriuretic peptide receptors in the rat tongue and hard palate. 975 43

The natriuretic peptide receptor (NPR) family consists of three receptor subtypes: two transmembrane forms that contain a guanylyl cyclase intracellular domain (NPR-A and NPR-B), and one truncated form (NPR-C). Because of the lack of specific agonists and antagonists for each receptor subtype and to the difficulty to detect the presence of small quantities of NPR-B by ligand binding studies, polyclonal antibodies against a peptide whose sequence was chosen from a region of the extracellular domain of rat NPR-B that is not homologous to sequences in NPR-A and NPR-C were developed. Western blotting with affinity-purified anti-NPR-B (413-426)-Tyr revealed a polypeptide of approximately 120 kD on COS-1 cell membranes transfected with rat NPR-B cDNA. The antibody recognized a second polypeptide, approximately 5 to 10 kD smaller, which probably represents the unglycosylated receptor. Anti-NPR-B (413-426)-Tyr did not show crossreactivity to any other NPR. Western blotting analysis with anti-NPR-B (413-426)-Tyr also identified a protein of appropriate size in renal vascular membranes. These results were supported by immunohistochemistry findings that demonstrated staining for NPR-B on papillary and medullary capillaries, glomeruli, and renal arteries. This study concludes that NPR-B is present in the rat kidney, although it was only detected in vascular structures.
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PMID:Immunolocalization of natriuretic peptide receptor B in the rat kidney. 977 78

Estrogen is known to exert both long-term genomic and short-term nongenomic actions. The long-term genomic actions of estrogen are mediated by the binding of estrogen to its cytoplasmic/nuclear receptor that subsequently triggers the transcription of target genes. In contrast, little is known about the molecular basis of the nongenomic actions of estrogen. We have found that 17-beta estradiol activates membrane-bound guanylate cyclase and enhances atrial natriuretic factor (ANF)-stimulated guanylate cyclase activity in PC12 cell membranes. Membrane-bound guanylate cyclase, GC-A, contains an extracellular ANF-binding domain and an intracellular kinase-like domain plus catalytic domain. The kinase-like domain plus the catalytic domain of guanylate cyclase (GC-kc) can be expressed in E. Coli and functionally renatured. 17-beta estradiol also activates the bacteria expressed GC-kc, indicating that 17-beta estradiol can directly interact with membrane-bound guanylate cyclase. These results demonstrate that 17-beta estradiol exerts a non-genomic action on membrane-bound guanylate cyclase.
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PMID:Stimulation of membrane-bound guanylate cyclase activity by 17-beta estradiol. 983 59

C-type natriuretic peptide (CNP) is a 22-amino-acid peptide, structurally related to but genetically distinct from atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whereas ANP and BNP are ligands for a guanylyl cyclase-coupled receptor, the NPR-A receptor, CNP is a specific ligand for the NPR-B receptor. In addition to clearance by the NPR-C receptor, CNP is subject to degradation by the ectoenzyme neutral endopeptidase 24.11 (NEP), which is widely distributed in the kidney, lung, heart, and endothelial cells. Although initially identified in porcine brain, CNP immunoreactivity has been found in human vascular endothelial cells, plasma, and kidney. CNP has potent systemic cardiovascular actions, which include reductions in cardiac filling pressures and output, secondary to vasorelaxation and decreases in venous return, but has minimal renal actions. Unlike ANP, CNP is a selective endothelium-independent venodilator. However, it is also a potent coronary vasodilator. Expression of the CNP gene by the endothelial cells, the presence of CNP receptors on vascular smooth muscle cells (VSMCs), and the antimitogenic effect of CNP on VSMCs suggest that CNP is produced by the endothelium and acts on adjacent VSMCs serving as an autocrine/paracrine endothelium-derived vasoregulatory system.
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PMID:C-type natriuretic peptide: the endothelial component of the natriuretic peptide system. 988 43

We isolated the cDNA and genomic DNA encoding a membrane guanylyl cyclase of medaka fish (designated as OlGC6), and determined their complete nucleotide sequences. The open reading frame for OlGC6 cDNA predicted a protein of 1,075 amino acids. Phylogenetic analysis indicated that OlGC6 is a member of the enterotoxin/guanylin receptor family. We also determined the partial genomic structure of the gene of another membrane guanylyl cyclase of medaka fish, OlGC2, which is a member of the natriuretic peptide receptor family. The intron positions relative to the protein-coding sequence are highly conserved in the intracellular domains of OlGC6, OlGC2, mammalian GC-A, and GC-E. Despite their divergent primary structures, some intron positions also seem to be conserved in the extracellular domains of different membrane guanylyl cyclase genes. Northern blot analysis demonstrated that an OlGC6 transcript of 3.9 kb is only present in the intestine, while reverse transcription (RT)-PCR analysis demonstrated that the OlGC6 transcript is present in the kidney, spleen, liver, pancreas, gallbladder, ovary, testis, brain, and eye. RT-PCR also demonstrated that OlGC6 is only expressed zygotically and that transcripts are present from 1 day after fertilization, i.e. long before the intestinal tissues begin to develop.
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PMID:Sequence analysis of cDNA and genomic DNA, and mRNA expression of the medaka fish homolog of mammalian guanylyl cyclase C. 1005 35

We investigate the interaction of atrial natriuretic peptide (ANP) brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) with their receptors (NPRA, NPRB and NPRC), as well as the proportion and localization of those receptors in the rat ciliary body. Binding assays and affinity cross-linking experiments demonstrated the presence of the NPRC receptor type. However, the three natriuretic peptides stimulate the guanylate cyclase activity in the ciliary body membranes suggesting the presence of the NPRA and NPRB receptor type. Microautoradiographic data show that the NPRs are localized in the whole ciliary body. Our results indicated that NPRC is the most prominent receptor type in this tissue.
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PMID:Higher proportions of type C than of types A and B natriuretic peptide receptors exist in the rat ciliary body. 1021 76


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