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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic factor (ANF)-dependent guanylate cyclase is a single-chain transmembrane-spanning protein, containing an ANF receptor and having catalytic activity. ANF binding to the receptor domain activates the catalytic domain, generating the second messenger cyclic GMP. Obligatory in this activation process is an intervening step regulated by ATP, but its mechanism is not known. Through a programme of site-directed and deletion mutagenesis/expression studies, we report herein the identity of a structural motif (Gly503-Arg-Gly-Ser-Asn-Tyr-Gly509) that binds ATP and amplifies the ANF-dependent cyclase activity; this, therefore, represents an ATP-regulatory module (ARM) of the enzyme, which plays a pivotal role in ANF signalling.
...
PMID:A structural motif that defines the ATP-regulatory module of guanylate cyclase in atrial natriuretic factor signalling. 134 81

Phenotype, growth, and functional characteristics of glomerular mesangial "myofibroblasts" are under the control of multiple hormones, vasoactive agents, autacoids, and cytokines. Several parallel signal transduction pathways couple receptor occupancy with functional changes, including phospholipases C, A2, and D breakdown of membrane phospholipids, and adenylate/guanylate cyclase activation. Changes of cytosolic ion concentrations, cyclic nucleotide accumulation, and eicosanoid biosynthesis are currently interpreted as intracellular signals for protein kinase activation. Phosphorylation of multiple substrates by serine/threonine kinases C, A, and G or by tyrosine kinases directly coupled to receptors, is a final step in cell activation. Cross-talk between signal transduction pathways, along with the release of eicosanoids and cytokines acting as intercellular mediators, provides the potential for interactive regulation of glomerular cell functions.
...
PMID:Signal transduction in mesangial cells. 135 Sep 29

The natriuretic peptide receptors (NPRs) are a family of three cell surface glycoproteins, each with a single transmembrane domain. Two of these receptors, designated NPR-A and NPR-B, are membrane guanylyl cyclases that synthesize cGMP in response to hormone stimulation. The third receptor, NPR-C, has been reported to function in the metabolic clearance of ligand and in guanylyl cyclase-independent signal transduction. We engineered three chimeric proteins consisting of the natriuretic peptide receptor extracellular domains fused to the Fc portion of human IgG-gamma 1. These molecules provide material for detailed studies of the human receptor's extracellular domain structure and interaction with the three human natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type-C natriuretic peptide (CNP). The homodimeric fusion proteins, designated A-IgG, B-IgG, and C-IgG, were secreted from Chinese hamster ovary cells and purified by protein-A affinity chromatography. We present here the primary characterization of these fusion proteins as represented by the intrinsic hormone affinities measured by saturation binding and competition assays. The dissociation constant of 125I-ANP for A-IgG was 1.6 pM and for C-IgG, 1.2 pM. The dissociation constant of 125I-Y0-CNP (CNP with addition of tyrosine at the amino terminus) for B-IgG was 23 pM. The rank order of potency in competitive binding for A-IgG was ANP greater than BNP much greater than CNP, whereas for B-IgG the ranking was CNP much greater than ANP greater than BNP. For C-IgG, we observed ANP greater than CNP greater than or equal to BNP. These data demonstrate that the receptor-IgG fusion proteins discriminate among the natriuretic peptides in the same manner as the native receptors and provide a basis for future structural studies with these molecules. The purified fusion proteins have a variety of potential applications, one of which we illustrate by a solid phase screening assay in which rabbit sera from a series of synthetic-peptide immunizations were titered for receptor reactivity and selectivity.
...
PMID:Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera. 166 Apr 65

There are four main classes of membrane-bound receptors: receptors which are also enzymes (tyrosine protein-kinase or guanylate cyclase), receptor channels, receptors coupled to G proteins (GTP binding proteins) and receptors with unknown transduction mechanisms. Receptors coupled to G proteins which have been cloned, constitute a superfamily of proteins containing seven hydrophobic transmembrane helices. The binding site of the ligand is within the hydrophobic core of the protein and the domain of interaction of the G proteins is constituted by the N- and C-terminal parts of the third intracellular loop, plus the C-terminal tail, adjacent to the transmembrane VII. G proteins themselves are also members of another superfamily. These proteins have highly conserved domains constituting the GTP binding site and they interact with the receptors by their C-terminal parts. Compounds such as mastoparan, substance P and 48/80 directly stimulate G proteins, an action which probably mediates their exocytotic properties. A high degree of homologies between G protein-linked receptors explains the non-specificity of some antagonists (like beta-adrenergic blocking agents on 5-HT1 receptors). The discovery of new members of the G protein-linked receptors which have not yet been pharmacologically characterized, raises the problem of receptor classification.
...
PMID:Coupling of receptors to G proteins, pharmacological implications. 166 41

Forty-eight hours after partial (approximately 67%) hepatectomy the activity of the particulate guanylate cyclase was increased by 2-fold in the regenerating rat liver. This increase was not an artifact of membrane isolation procedures, and as determined by 125I-labeled Tyr-28 atrial natriuretic hormone-(1-28) ANF binding, was accompanied by a 2-fold increase in the number of ANF receptors. The Kd of the receptors in membranes of regenerating livers was not significantly different from the Kd of the receptors in livers of sham-operated rats. The linear synthetic descysteine analog of ANF, analog I, which binds only to the 66-kDa receptors, displaced approximately 40% of the specifically bound 125I-ANF in liver membranes from both hepatectomized and sham-operated (control) animals. Affinity cross-linking studies with 125I-ANF confirmed the increase in the 116-kDa ANF receptor in membranes of regenerating livers. In perfused livers derived from control and hepatectomized animals, the basal rates of cGMP production were not significantly different. However, atriopeptin II-stimulated cGMP production was twice as great in regenerating livers as compared with controls. These data demonstrate that the increase in particulate guanylate cyclase activity observed during liver regeneration is due to an increase in the 116-kDa ANF receptor-associated activity. Additionally, our data demonstrate that the regenerating rat liver may be a valuable model with which to study the role of the hepatic ANF receptor/particulate guanylate cyclase.
...
PMID:Increase in the number of atrial natriuretic hormone receptors in regenerating rat liver. 167 Jul 70

The cyclic GMP-forming enzyme guanylyl cyclase exists in cytosolic and in membrane-bound forms differing in structure and regulations. Determination of the primary structures of the guanylyl cyclases revealed that the cytosolic enzyme form consists of two similar subunits and that membrane-bound guanylyl cyclases represent enzyme forms in which the catalytic part is located in an intracellular, C-terminal domain and is regulated by an extracellular, N-terminal receptor domain. A domain of 250 amino acids conserved in all guanylyl cyclases appears to be required for the formation of cyclic nucleotide, as this homologous domain is also found in the cytosolic regions of the adenylyl cyclase. The general structures of guanylyl cyclases shows similarities with other signal transducing enzymes such as protein-tyrosine phosphatases and protein-tyrosine kinases, which also exist in cytosolic and receptor-linked forms.
...
PMID:Sequence homologies between guanylyl cyclases and structural analogies to other signal-transducing proteins. 167 55

In vitro autoradiographic studies showed that high-affinity atrial natriuretic factor (ANF) binding sites are present on rat choroid plexus (Kd = 83.8 pM, Bmax = 22.9 fmol/mg protein). Guanylate cyclase-coupled receptors (ANF-R1) represent 30% and non-guanylate cyclase-coupled ANF receptors (ANF-R2) represent 70% of the total ANF receptors present in this tissue. To provide detailed cellular localization of the binding sites, the technique of electron-microscopic autoradiography was applied using 125I-ANF (Ser 99-Tyr 126) as an in vivo ligand. In order to identify possible binding sites at the basolateral and the apical aspects of the choroid plexus, the ligand was injected into the carotid artery or into the lateral cerebral ventricles, respectively. Light-microscopic autoradiography demonstrated that ANF binds specifically to choroid plexus regardless of its route of administration. Electron-microscopic autoradiography showed that silver grains were localized primarily on epithelial cells of the choroid plexus (96-99%) and marginally on endothelial and pial cells. In choroidal epithelial cells, ultrastructural analysis of silver grain distribution revealed that, at 2 min after intracarotid or intracerebroventricular 125I-ANF injection, lysosomes were the most distinctly labeled organelle (highest relative specific radioactivity). HPLC Chromatographic analysis disclosed that 96-99% of choroid plexus-bound ANF was already degraded 2 min after injection and that at least 63-66% of the degradation took place at the plasma membrane. These results indicate that ANF binding sites are present on both aspects of choroidal epithelium, and suggest that ANF is very quickly degraded in choroid plexus by membrane-associated as well as lysosome-associated processes.
...
PMID:Localization and characterization of binding sites for circulating and cerebroventricular atrial natriuretic factor in rat choroid plexus. 215 94

The response to small peptides such as Arg-vasopressin, oxytocin and tachykinins was investigated in cultured porcine aortic endothelial cells. The production of endothelium-derived nitric oxide was assessed indirectly by the accumulation of cyclic GMP, a response that is due to the increased activity of soluble guanylate cyclase of the endothelial cells after release of the mediator. Arg-vasopressin, oxytocin, substance P and physalae-min (an analog of substance P, pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Gly-Leu-Met-NH2) markedly and transiently stimulated the production of cyclic GMP without affecting that of cyclic AMP. Treatment of endothelial cells with either hemoglobin or methylene blue reduced significantly both the basal and stimulated level of cyclic GMP. The production of cyclic GMP evoked by Arg-vasopressin and substance P was inhibited selectively by NG-monomethyl-L-arginine but not by its D-enantiomer. The neurohypophyseal hormones and related peptides stimulated the accumulation of cyclic GMP in a concentration-dependent manner, with the following relative order of potency: oxytocin greater than Lys-vasopressin greater than Arg-vasopressin much greater than [deamino-Cys1, D-Arg8]-vasopressin. The production of cyclic GMP evoked by oxytocin was inhibited selectively by [d(CH2)5, Tyr(OMe)2, Orn8]-vasotocin, an oxytocin antagonist. The production of cyclic GMP evoked by Arg-vasopressin and Lys-vasopressin was inhibited by [beta-mercapto-beta, beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8]-vasopressin, a selective V1-receptor antagonist. The moderate production of cyclic GMP evoked by [deamino-Cys1, D-Arg8]-vasopressin was inhibited significantly by the V1-receptor antagonist. The peptide antagonists affected only minimally or not at all the production of cyclic GMP evoked by a donor of nitric oxide, SIN-1 (3-Morpholino-Sydnonimine). These observations indicate that 1) neurohypophyseal hormones and tachykinins stimulate the accumulation of cyclic GMP in cultured porcine aortic endothelial cells by increasing the production of endothelial-derived nitric oxide, which in turn enhances the activity of soluble guanylate cyclase; 2) the production of cyclic GMP in response to oxytocin is due to activation of oxytocinergic receptors; and 3) the production of cyclic GMP evoked by Arg-vasopressin and Lys-vasopressin is due mostly to activation of V1-vasopressinergic receptors.
...
PMID:Neurohypophyseal peptides and tachykinins stimulate the production of cyclic GMP in cultured porcine aortic endothelial cells. 217 9

Rat thoracic aortic smooth muscle cells (line A10, ATCC CRL 1476) display a high density of atrial natriuretic factor (ANF) receptors. ANF stimulated the accumulation of cGMP in these cells in a time- and dose-dependent fashion. These cells are known to display a high density of vasopressin receptors of the vascular V1 subtype. These vasopressin receptors mediate inhibition of isoproterenol-stimulated cAMP accumulation and stimulation of inositol phosphate accumulation and calcium fluxes. Addition of [8-arginine]vasopressin ([Arg8]VP) to these cells inhibited ANF-stimulated cGMP accumulation. Inhibition of cGMP accumulation was dependent on the concentration of [Arg8]VP, with half-maximal and maximal effects occurring at 0.4 and 10 nM, respectively. [Arg8]VP did not have significant effects on basal cGMP levels. The inhibition by [Arg8]VP appears to be mediated by V1 receptors, since the V2 renal receptor agonist [1-desaminocysteine,8-D-arginine]vasopressin was ineffective. Also, the selective V1 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-methyltyrosine),8-arginine]vasopressin and the mixed V1/V2 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-ethyl-D-tyrosine),4-valine,8-arginine]vasopressin blocked the [Arg8]VP-mediated effect, whereas the selective V2 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-D-isoleucine,4-valine,8-arginine]vasopressin was minimally effective. These data show that in rat aortic smooth muscle cells, V1 receptors are negatively coupled to guanylate cyclase. These data also suggest that the vasoconstrictor activity of [Arg8]VP might involve inhibition of ANF-receptor-mediated vascular relaxation through inhibition of cGMP accumulation in addition to its effects on isoproterenol-mediated cAMP accumulation and inositol phosphate accumulation and calcium fluxes.
...
PMID:Vasopressin-mediated inhibition of atrial natriuretic factor-stimulated cGMP accumulation in an established smooth muscle cell line. 243 Feb 90

Guanylate cyclase appears to represent a central member of a diverse family of proteins involved in cell signaling mechanisms including the protein kinases, a low Mr ANP receptor, and possibly adenylate cyclase (based on limited sequence identity with the yeast enzyme). A membrane form of guanylate cyclase represents a new model for cell surface receptors, although such a model was once envisioned for adenylate cyclase (79). In original models for adenylate cyclase, hormone was thought to bind with either the enzyme or with an unknown protein to enhance cyclic AMP production (79). Guanylate cyclase appears to fall into the first adenylate cyclase model where binding of a ligand to an extracellular site on the enzyme transmits a signal to an intracellular catalytic site. The production of cyclic GMP, a second messenger, and of pyrophosphate are then increased. The protein tyrosine kinase family of receptors (80) and possibly another forthcoming family of cell surface receptors containing protein tyrosine phosphatase activity (81-83) contain a single transmembrane domain like guanylate cyclase. Furthermore, the protein tyrosine kinases are activated by ligand binding to the extracellular domain. However, the activation of guanylate cyclase, unlike these cell surface receptors, results in the formation of a low molecular weight second messenger.
...
PMID:Guanylate cyclase, a cell surface receptor. 256 11


1 2 3 4 5 6 7 8 9 10 Next >>

---