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)

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.
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PMID:Coupling of receptors to G proteins, pharmacological implications. 166 41

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.
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PMID:Sequence homologies between guanylyl cyclases and structural analogies to other signal-transducing proteins. 167 55

Particulate guanylate cyclase (GTP pyrophosphate-lyase (cyclizing] has been cytochemically evidentiated in the cells which make-up the lung air-blood barrier. The cytochemical procedure utilized demonstrates the presence of membrane-bound guanylate cyclase activity through precipitation of lead pyrophosphate in tissues incubated with GTP or with guanylyl imidodiphosphate. Electron microscopic examination reveals that guanylate cyclase (GC) is localized, as micropinocytic vesicles, within endothelial components of small blood vessels, in basal lamina and in the flat alveolar cells. The secretory alveolar cells also exhibit the positive GC reactivity in their peripheric cytoplasm and in their microvilli. The observations support that GC and cGMP are involved in cellular transport phenomena. The enzyme might play a role in the secretion process of surface active material. Positive staining has been found also in other types of cells, namely alveolar macrophages and fibroblasts. A biochemical evaluation of GC activity shows that about 30-40% of this activity is associated with the particulate fraction, which justifies its abundance in the cytochemical reports shown in the paper.
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PMID:Cytochemical and biochemical observations on the alveolar guanylate cyclase of golden hamster lung. 167 93

Characterization of the serotonin (5-HT)-induced cyclic GMP (cGMP) elevation was investigated in comparison with bradykinin- and ANP-induced elevations in NG108-15 cells. At 20 s, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM, 100 microM), a membrane-permeabilized Ca2+ chelator, or N-monomethyl-L-arginine (NMMA, 300 microM), an inhibitor of L-arginine-derived nitric oxide (NO) synthesis, inhibited 5-HT-induced elevation by approximately 40%, and completely inhibited bradykinin-induced response. Neither 5-HT- nor ANP-induced cGMP elevation at 10 min was affected by BAPTA-AM or NMMA. The cGMP elevated by 5-HT as well as by ANP was effluxed to the extracellular medium. These results and our previous report suggest that 5-HT stimulates two subtypes of 5-HT receptors in NG108-15: first, 5-HT3 subtype stimulating Ca(2+)-sensitive cytosolic guanylate cyclase through NO derived from L-arginine and second, a probably novel 5-HT receptor subtype involved in activation of membrane-bound guanylate cyclase.
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PMID:The slow cyclic GMP increase caused by serotonin in NG108-15 cells is not inhibited by antagonists of known serotonin receptors: possible existence of a new receptor subtype coupled with membrane-bound guanylate cyclase. 167 31

The stereochemical course of the reaction catalyzed by guanylate cyclase from bovine retinal rod outer segments was investigated using phosphorothioate analogs of GTP as chiral probes. (Sp)-Guanosine 5'-O-(1-thiotriphosphate) (Sp-GTP alpha S) is a substrate, whereas (Rp)-GTP alpha S is a competitive inhibitor (K1 = 0.1 mM), but not a substrate. (Sp)-GTP alpha S is converted into (Rp)-guanosine 3':5'-monophosphorothioate, showing that the reaction proceeds with inversion of configuration at the alpha-phosphorus atom. Km and Vmax for (Sp)-GTP alpha S (at low [Ca2+], 20 nM) are 3.7 mM and 1.1 nmol/min/mg of rhodopsin, respectively, compared with 1.1 mM and 23.1 nmol/min/mg of rhodopsin for GTP. Vmax for the cyclization of (Sp)-GTP alpha S, as for GTP, increases 10-20-fold when the calcium level is lowered. This activity change is centered at approximately 90 nM and has a Hill coefficient of 4.8. The configuration of the metal-substrate complex was determined by measuring the effectiveness of the Sp and Rp isomers of GTP alpha S and guanosine 5'-O-(2-thiotriphosphate) (GTP beta S) in the presence of Mg2+ or Mn2+. (Sp)-GTP alpha S is a substrate with either Mg2+ or Mn2+, whereas (Rp)-GTP beta S is a substrate with only Mn2+. These findings suggest that the substrate is a metal-beta, gamma-bidentate complex with delta screwsense. We also found that the cyclization reaction catalyzed by the membrane-bound guanylate cyclase from sea urchin sperm proceeds with inversion of configuration at the alpha-phosphorus atom. The stereochemical course of the reactions catalyzed by all prokaryotic and eukaryotic adenylate cyclases and guanylate cyclases studied thus far is the same.
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PMID:Stereochemical course of the reaction catalyzed by guanylate cyclase from bovine retinal rod outer segments. 197 55

The potent diuretic and natriuretic peptide hormone atrial natriuretic factor (ANF), with vasodilatory activity also stimulates steroidogenic responsiveness in Leydig cells. The actions of ANF are mediated by its interaction with specific cell surface receptors and the membrane-bound form of guanylate cyclase represents an atrial natriuretic factor receptor (ANF-R). To understand the mechanism of ANF action in testicular steroidogenesis and to identify guanylate cyclase/ANF-R that is expressed in the Leydig cells, the primary structure of murine guanylate cyclase/ANF-R has been deduced from its cDNA sequence. A cDNA library constructed from poly(A+) RNA of murine Leydig tumor (MA-10) cell line was screened for the membrane-bound form of ANF-R/guanylate cyclase sequences by hybridization with a rat brain guanylate cyclase/ANF-R cDNA probe. The amino acid sequence deduced from the cDNA shows that murine guanylate cyclase/ANF-R cDNA consists of 1057 amino acids with 21 amino acids comprising the transmembrane domain which separates an extracellular ligand-binding domain (469 amino acid residues) and an intracellular guanylate cyclase domain (567 amino acid residues). Upon transfection of the murine guanylate cyclase/ANF-R cDNA in COS-7 cells, the expressed protein showed specific binding to 125I-ANF, stimulation of guanylate cyclase activity and production of intracellular cGMP in response to ANF. The expression of guanylate cyclase/ANF-R cDNA transfected in rat Leydig tumor cells stimulated the production of testosterone and intracellular cGMP after treatment with ANF. The results presented herein directly show that ANF can regulate the testicular steroidogenic responsiveness in addition to its known regulatory role in the control of cardiovascular homeostasis.
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PMID:Molecular cloning and expression of murine guanylate cyclase/atrial natriuretic factor receptor cDNA. 197 87

The present investigation describes kinetic characteristics of membrane-bound and Triton X-100-solubilized atrial natriuretic factor (ANF)-sensitive guanylate cyclase from bovine adrenal cortex. The kinetic analysis of both enzyme forms suggests that in the presence of manganese, ANF induces or stabilizes at least two apparent GTP*Mn2(+)- and in addition two Mn2(+)-binding sites. Addition of the natriuretic drug amiloride favors this state. ATP increases the vmax in the presence of ANF for GTP*Mg2+, but not for GTP*Mn2+ as a substrate. With GTP*Mg2+, amiloride has no effect on basal or ANF-stimulated activity, but slightly reduces the effect of ATP. Under all conditions tested, the enzyme follows regular Michaelis-Menten kinetics in the presence of Mg2+ and exhibits positive cooperativity with Mn2+. Positive cooperativity is also retained after Triton extraction. The results indicate that Triton extraction has no major influence on the kinetic properties of particulate guanylate cyclase when the extraction procedure is done carefully. The data also support the suggestion that multiple interactions of subunits might occur upon activation of the enzyme by ANF in the presence of Mn2+.
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PMID:Kinetic characterization of atrial natriuretic factor-sensitive particulate guanylate cyclase. 198 Jun 49

STa, the heat-stable enterotoxin of Escherichia coli, stimulates membrane-bound guanylate cyclase in enterocytes, elevates cyclic GMP, and results in intestinal secretion of ions and fluid. Using the T84 colon carcinoma cell line as a model. Weikel et al. reported that phorbol esters enhance STa-stimulated cyclic GMP production by 60-140% [(1990) Infect. Immun. 58, 1402-1407]. In the present report we demonstrate that the acetylcholine analog carbachol enhanced toxin-stimulated cyclic GMP accumulation in intact T84 cells by 50-100% and that this effect was blocked by 10 microM atropine and 10 microM sphingosine. Pertussis toxin treatment of the T84 cells did not affect the subsequent response to carbachol. Carbachol, which elevates intracellular calcium in these cells, may act through protein kinase C to enhance cyclic GMP production.
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PMID:Carbachol mimics phorbol esters in its ability to enhance cyclic GMP production by STa, the heat-stable toxin of Escherichia coli. 217 3

Cytidylate cyclase was demonstrated to be distributed in various tissues of rat, with the highest activity in brain, and it was shown to be a membrane-bound type enzyme. The enzyme was effectively dispersed from the membrane fraction of rat brain with 0.3% (w/v) Triton X-100. The dispersed cytidylate cyclase had an optimal pH of 9.4 and the activity at a physiological pH of 7.5 was less than 20% of the maximum value. This enzyme completely lost its activity in the absence of divalent cation such as Mn2+ and Mg2+. The Km value for CTP was calculated as 0.0156 mM, by Lineweaver-Burk analysis. It was also found that activity of dispersed enzyme was inhibited by ATP, but not GTP. Both forskolin and lanthanum chloride, which affect adenylate cyclase, showed no effect on cytidylate cyclase. These results indicate that cytidylate cyclase is a unique membrane-bound enzyme distinct from purine nucleotide cyclases, adenylate cyclase and guanylate cyclase.
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PMID:Characterization of detergent dispersed cytidylate cyclase of rat brain. 228 31

In order to obtain more insight into the possible role of cyclic AMP or cyclic GMP in modulating the initial cellular processes following activation of lymphocytes, we measured the effects of the T-cell mitogen concanavalin A and other substances including hormones on the cyclic nucleotide levels in human peripheral blood lymphocytes. The enzyme activities of the corresponding nucleotide cyclases, adenylate cyclase and guanylate cyclase were measured in both isolated plasma membranes or the cytosol of resting or concanavalin A stimulated rabbit thymocytes. Concanavalin A in a mitogenic concentration of about 5-10 micrograms/ml caused small, but consistent increases in cAMP but no changes in cGMP levels during the first hour of activation. Concomitantly, the specific activity of plasma membrane-bound adenylate cyclase was always increased at least 1.5-fold 30 min after stimulation of rabbit thymocytes with concanavalin A, but no effect could be detected on the specific activities of plasma membrane-bound or soluble guanylate cyclase. At high, supraoptimal concentrations of concanavalin A (more than 20 micrograms/ml) cAMP levels dramatically increased in human lymphocytes within minutes, but cGMP levels again were unaffected. Forskolin and beta-adrenergic hormones elevated cAMP in human lymphocytes, whereas cGMP levels were increased by the addition of sodium nitroprusside or alpha-adrenergic hormones. Sodium nitroprusside, in concentrations which elevated cGMP in human lymphocytes, had no influence on the incorporation of [3H]uridine into RNA of resting or concanavalin A stimulated human lymphocytes. Addition of forskolin resulted in an increase of cAMP levels and a dose-dependent decrease of [3H]uridine incorporation into RNA of concanavalin A-stimulated lymphocytes with no effect on resting lymphocytes. The data suggest that cGMP does not play a role in the initial phase of mitogenic activation of lymphocytes, whereas cAMP may be involved in the blast transformation process as an inhibitory signal.
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PMID:Are cyclic nucleotides involved in the initiation of mitogenic activation of human lymphocytes? 241 Dec 97


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