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 generation and function(s) of the signalling molecule cyclic GMP (cGMP) in brain are still poorly understood. One mechanism to raise intracellular cGMP levels is binding of C-type natriuretic peptide (CNP) to a membrane guanylyl cyclase (GC), termed GC-B. Here, we demonstrate an exceptionally strong expression of GC-B in the pineal gland. Crosslinking experiments performed with 125I-Tyr(0)-CNP and membranes from various rat tissues identified the receptor as a 130-kDa protein, expressed at highest levels in pineal membranes. Receptor autoradiography on brain sections confirmed a striking density of CNP binding sites in pineal tissue, whereas binding sites for the related atrial natriuretic peptide (ANP) predominate in other regions of the brain. Incubations of freshly dissected whole pineal glands in either the absence or presence of natriuretic peptides followed by immunohistochemical analyses of cGMP revealed strong accumulations of cGMP in response to CNP but not to ANP in the majority of pinealocytes. Stimulation of soluble GC (sGC) activity by use of sodium nitroprusside (SNP) resulted in a very similar pattern of cGMP immunostaining, indicating a co-expression at high levels of particulate and soluble forms of GC. These findings point to a major role of cGMP signalling in pinealocytes and suggest an important regulatory function for CNP.
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PMID:Guanylyl cyclase-B represents the predominant natriuretic peptide receptor expressed at exceptionally high levels in the pineal gland. 1068 54

C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, has been found at its highest tissue concentrations in the anterior pituitary, where it is localised in gonadotrophs. Its specific guanylyl cyclase-containing receptor, GC-B, is also expressed on several anterior pituitary cell types, and CNP potently stimulates cGMP accumulation in rat pituitary cell cultures and pituitary cell lines. The mouse gonadotroph-derived alpha T3-1 cell line has been shown to express CNP as well as GC-B (but not GC-A) receptors, suggesting that CNP may well be an autocrine regulator of gonadotrophs. Comparing effects of three natriuretic peptides (atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and CNP) on cGMP accumulation in four pituitary cell lines (alpha T3-1, TtT-GF, AtT-20 and GH(3)) we find that CNP is most potent and effective in alpha T3-1 cells. In these cells, CNP-stimulated cGMP accumulation was found to desensitise during a 30 min exposure to CNP. Pretreatment with CNP for up to 6 h also caused a significant reduction in the ability of CNP to subsequently stimulate cGMP accumulation. This effect was receptor specific, because pretreatment with sodium nitroprusside (an activator of nitric oxide-sensitive guanylyl cyclase), or with ANP or BNP, did not cause desensitisation of CNP-stimulated cGMP accumulation. Protein kinase C activation with phorbol esters also inhibited CNP-stimulated cGMP accumulation and such inhibition was also seen in cells desensitised by pretreatment with CNP. Thus it appears that the endogenous GC-B receptors of alpha T3-1 cells are subject to both homologous and heterologous desensitisation, that the mechanisms underlying these forms of desensitisation are distinct, and that cGMP elevation alone is insufficient to desensitise GC-B receptors.
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PMID:C-type natriuretic peptide (CNP) effects in anterior pituitary cell lines: evidence for homologous desensitisation of CNP-stimulated cGMP accumulation in alpha T3-1 gonadotroph-derived cells. 1085 98

Single-transmembrane natriuretic peptide clearance receptor (NPR-C), which is devoid of a cytoplasmic guanylyl cyclase domain, interacts with pertussis toxin (PTx)-sensitive G proteins to activate endothelial nitric oxide synthase (eNOS) expressed in gastrointestinal smooth muscle cells. We examined the ability of NPR-C to activate other effector enzymes in eNOS-deficient tenia coli smooth muscle cells; these cells expressed NPR-C and NPR-B but not NPR-A. Atrial natriuretic peptide (ANP), the selective NPR-C ligand cANP-(4-23), and vasoactive intestinal peptide (VIP) inhibited (125)I-ANP and (125)I-VIP binding to muscle membranes in a pattern indicating high-affinity binding to NPR-C. Interaction of VIP with NPR-C was confirmed by its ability to inhibit (125)I-ANP binding to membranes of NPR-C-transfected COS-1 cells. In tenia muscle cells, all ligands selectively activated G(i-1) and G(i-2); VIP also activated G(s) via VIP(2) receptors. All ligands stimulated phosphoinositide hydrolysis, which was inhibited by ANP-(1-11), PTx, and antibodies to phospholipase C-beta3 (PLC-beta3) and Gbeta. cANP-(4-23) contracted tenia muscle cells; contraction was blocked by U-73122 and PTx and by antibodies to PLC-beta3 and Gbeta in intact and permeabilized muscle cells, respectively. VIP and ANP contracted muscle cells only after inhibition of cAMP- and cGMP-dependent protein kinases. ANP and cANP-(4-23) inhibited forskolin-stimulated cAMP in a PTx-sensitive fashion. We conclude that NPR-C is coupled to activation of PLC-beta3 via betagamma-subunits of G(i-1) and G(i-2) and to inhibition of adenylyl cyclase via alpha-subunits.
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PMID:G(i-1)/G(i-2)-dependent signaling by single-transmembrane natriuretic peptide clearance receptor. 1085 28

The binding of atrial natriuretic peptide and C-type natriuretic peptide (CNP) to the guanylyl cyclase-linked natriuretic peptide receptors A and B (NPR-A and -B), respectively, stimulates increases in intracellular cGMP concentrations. The vasoactive peptides vasopressin, angiotensin II, and endothelin inhibit natriuretic peptide-dependent cGMP elevations by activating protein kinase C (PKC). Recently, we identified six in vivo phosphorylation sites for NPR-A and five sites for NPR-B and demonstrated that the phosphorylation of these sites is required for ligand-dependent receptor activation. Here, we show that phorbol 12-myristate 13-acetate, a direct activator of PKC, causes the dephosphorylation and desensitization of NPR-B. In contrast to the CNP-dependent desensitization process, which results in coordinate dephosphorylation of all five sites in the receptor, phorbol 12-myristate 13-acetate treatment causes the dephosphorylation of only one site, which we have identified as Ser(523). The conversion of this residue to alanine or glutamate did not reduce the amount of mature receptor protein as indicated by detergent-dependent guanylyl cyclase activities or Western blot analysis but completely blocked the ability of PKC to induce the dephosphorylation and desensitization of NPR-B. Thus, in contrast to previous reports suggesting that PKC directly phosphorylates and inhibits guanylyl cyclase-linked natriuretic peptide receptors, we show that PKC-dependent dephosphorylation of NPR-B at Ser(523) provides a possible molecular explanation for how pressor hormones inhibit CNP signaling.
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PMID:Activation of protein kinase C stimulates the dephosphorylation of natriuretic peptide receptor-B at a single serine residue: a possible mechanism of heterologous desensitization. 1091 2

In the decade since its discovery, C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, has been shown to be produced by most of the major endocrine glands, including the hypothalamus and anterior pituitary. The relative abundance of its guanylyl cyclase-containing GC-B receptor in these glands suggests that CNP might be a local neuroendocrine regulator. Here, we review this possibility, emphasizing signalling and integration with other regulatory systems in the neuroendocrine control of reproduction.
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PMID:C-type natriuretic peptide: an important neuroendocrine regulator? 1099 29

The natriuretic peptides (NPs) constitute a family of polypeptide hormones that regulate mammalian blood volume and blood pressure. The ability of the NPs to modulate cardiac hypertrophy and cell proliferation as well is now beginning to be recognized. The NPs interact with three membrane-bound receptors, all of which contain a well-characterized extracellular ligand-binding domain. The R1 subclass of NP receptors (NPR-A and NPR-B) contains a C-terminal guanylyl cyclase domain and is responsible for most of the NPs downstream actions through their ability to generate cGMP. The R2 subclass lacks an obvious catalytic domain and functions primarily as a clearance receptor. This review focuses on the signal transduction pathways initiated by ligand binding and other factors that help to determine signalling specificities, including allosteric factors modulating cGMP generation, receptor desensitization, the activation and function of cGMP-dependent protein kinase (PKG), and identification of potential nuclear or cytoplasmic targets such as the mitogen-activated protein kinase signalling (MAPK) cascade. The inhibition of cardiac growth and hypertrophy may be an important but underappreciated action of the NP signalling system.
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PMID:Natriuretic peptide signalling: molecular and cellular pathways to growth regulation. 1130 39

This study investigated the hypothesis that atrial natriuretic peptide (ANP) responses are mediated by particulate guanylate cyclase in the pulmonary vascular bed of the cat. When tone in the pulmonary vascular bed was raised to a high steady level with the thromboxane mimic U-46619, injections of ANP caused dose-related decreases in lobar arterial pressure. After administration of HS-142-1, an ANP-A- and ANP-B-receptor antagonist, vasodilator responses to ANP were reduced. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) enhanced ANP vasodilator responses, suggesting that inhibition of NO modulates ANP responses. L-NAME administration with constant 8-bromo-cGMP infusion attenuated the increased vasodilator response to ANP, suggesting that supersensitivity to ANP occurs upstream to activation of a cGMP-dependent protein kinase. In pulmonary arterial rings, ANP produced concentration-related vasorelaxant responses with and without endothelium. Methylene blue, L-NAME, or N(omega)-monomethyl-L-arginine did not alter ANP vasorelaxant responses. These data show that ANP supersensitivity observed in the intact pulmonary vascular bed is not seen in isolated pulmonary arterial segments, suggesting that it may only occur in resistance vessel elements. These results suggest that ANP responses occur through activation of ANP-A and/or -B receptors in an endothelium-independent manner and are modulated by NO in resistance vessel elements in the pulmonary vascular bed of the cat.
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PMID:L-NAME enhances responses to atrial natriuretic peptide in the pulmonary vascular bed of the cat. 1135 72

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

Complementary DNA fragments for two isoforms of particulate guanylate cyclase C (GC-C) were cloned from the intestine of the European eel (Anguilla anguilla). Both isoforms exhibited higher nucleotide and amino acid sequence homologies to members of the GC-C family from other species than the related guanylate cyclase A or B (GC-A or GC-B) isoforms from the eel. Northern blots indicated that probes for both isoforms, termed GC-C1 and GC-C2, selectively hybridised to 4.8-kb transcripts in the intestine and the kidney. Expression of the GC-C2 transcript in the intestine was increased by 100% following the transfer of yellow FW-acclimated eels to SW. Likewise developmental maturation of yellow eels into pre-migratory silver eels resulted in a significant increase (60%) in the intestinal expression of GC-C2. No changes in expression of GC-C2 were seen in the kidney under any condition. RT-PCR indicated that the GC-C2 isoform is only expressed in anterior and mid-gut segments in FW-acclimated yellow eels. However, expression is also extended to the posterior gut segment when yellow eels are acclimated to SW or following developmental transformation into silver eels.
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PMID:Cloning and expression of two isoforms of guanylate cyclase C (GC-C) from the European eel (Anguilla anguilla). 1139 93

Two cDNA clones (OlGC2 and OlGC7) and their genomic DNA clones encoding medaka fish homologs of mammalian natriuretic peptide receptor/membrane guanylyl cyclase A (GC-A) were isolated, and their complete nucleotide sequences were determined. The open reading frame predicts a protein of 1,063 amino acids for OlGC2 cDNA (4,283 bp), and one of 1,055 amino acids for OlGC7 cDNA (3,721 bp), respectively. Northern blot analyses demonstrated 4.7 kb OlGC2 transcripts in the kidney and gill, and 4.0 kb OlGC7 transcripts in the kidney, brain, and ovary, while RNase protection analyses revealed that both genes are expressed in various adult organs. Both the OlGC2 (about 33.0 kbp) and OlGC7 (about 44.3 kbp) genes consist of 22 exons with an exon/intron organization similar to those of the human GC-A gene (about 16.6 kbp) and medaka fish GC-B homolog gene (OlGC1, about 93 kbp). Intron 4 of OlGC2 contains two repeated sequence (RS) clusters, designated as RS1 (about 1 kbp) and RS2 (about 5 kbp), consisting of nucleotide 5'-AGCCTCTGCTCCTCCTTC-3'. In addition, many identical but variably sized nucleotide sequences were found in introns in OlGC1, OlGC2, OlGC6, and OlGC7. The OlGC2 and OlGC7 genes both have no apparent TATA box in the 5' flanking region upstream of the putative transcription initiation point, but several consensus sequences for cis-regulatory elements, including C/EBP, CREB, NF-IL6, and Sp1 and AP-2, NF-IL6, c-Myb, and Sp1 are present in the 5'-flanking region of OlGC2 and OlGC7, respectively.
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PMID:Expression and exon/intron organization of two medaka fish homologs of the mammalian guanylyl cyclase A. 1143 78


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