Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transduction of a visual signal is a complex process. It involves photochemical, enzymatic and ionic reactions. An electrophysiological response is generated on absorption of a photon by a photoreceptor cell's pigment molecule, then propagates to the synapses. The first photochemical reaction, isomerization of retinal, in vertebrates occurs in the photoreceptor cells--rods and cones--of the retina, so changes conformation and activity of a pigment-bound protein, rhodopsin, in membranes of intracellular discs. Rhodopsin becomes enzymatically active and catalyses the activation by GTP of a great number of transducins, which in turn activate cGMP phosphodiesterase. This enzymatic chain propagates and greatly enhances hydrolysis of cytoplasmic cGMP. One photon incites hydrolysis of 10(5) cGMP molecules in 100 ms. Local cGMP decrease frees it from specific binding sites in cytoplasm occupied by proteinaceous canals in cell membrane around the activated disc. In darkness high cGMP concentration, hence binding, kept canals open, maintaining high cellular cation permeability, especially to Na+, and a strong cellular depolarization. Ca2+ influx, also allowed, balanced Na+ movement. Canal closure induces local hyperpolarization, the first electrophysiological response, which propagates through the cell to synaptic contacts. It also lowers intracellular Ca2+ concentration which initiates cGMP synthesis--from GTP by a guanylate cyclase controlled negatively by recoverin, a calcium-dependent protein--to restore cGMP towards at rest level. Although all macromolecules involved in this now fairly complete scheme have been isolated and characterized, cloned and sequenced, no three-dimensional structure has yet been established. The proteins are membrane-bound rather than in independent crystal form, which renders such structural studies difficult.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Transduction of the visual signal in retinal cells]. 142 99

Atrial natriuretic factor (ANF-R1) receptor is a 130-kDa protein that contains a cytoplasmic guanylate cyclase domain. We report that ATP interacts in an allosteric manner with the ANF-R1 receptor, resulting in reduced ANF binding and enhanced ANF-stimulated guanylate cyclase activity. The modulatory properties of various nucleotides indicate a preference for the adenine family with a rank order of potency of ATP greater than App(NH)p greater than or equal to ADP greater than or equal to AMP while cyclic and guanine nucleotides except GTP are inactive. The negative modulation by ATP of ANF binding is specific for the ANF-R1 receptor subtype since the amount of ANF bound by the guanylate cyclase uncoupled ANF-R2 subtype is increased in the presence of ATP. Furthermore, the effects of ATP on ANF-R1 receptor binding function are still observed with the affinity-purified ANF-R1 receptor, suggesting an allosteric binding site for ATP on the ANF-R1 receptor. In intact membranes, limited proteolysis of the ANF-R1 receptor with trypsin dose-dependently prevents the ATP-induced decrease in ANF binding concomitantly with the formation of a membrane-associated ANF-binding fragment of 70 kDa. These results confirm the direct modulatory role of ATP on hormone binding activity of ANF-R1 receptor and suggest that the nucleotide regulatory binding site is located in the intracellular domain vicinal to the protease-sensitive region.
 ...
PMID:Allosteric modulation by ATP of the bovine adrenal natriuretic factor R1 receptor functions. 165 83

Type A atrial natriuretic peptide (ANP) receptor was demonstrated to be present as a tetramer in the bovine adrenal cortex. Type A ANP receptor is composed of two functional domains, namely extracellular ANP-binding and cytoplasmic guanylate cyclase domains, and generally considered to be present as a single polypeptide chain of about 140 kDa based on its primary structure deduced from the cDNA sequence and its SDS/PAGE profile under reducing conditions. Characterization of the type A receptor or receptor/cyclase under non-reducing conditions led to the discovery stated in the title. The type A ANP receptor was partially purified from bovine adrenal cortex membranes by Blue-Sepharose and GTP-agarose chromatography. SDS-PAGE analysis of the receptor preparation revealed that although under reducing conditions it migrated as a 140-kDa band, the mobility of the receptor was greatly retarded in the absence of reducing agents, suggesting that the type A ANP receptor is present as a disulfide-linked oligomer in its native state. Further analysis using SDS-polyacrylamide-agarose gels suitable for determining the sizes of high-molecular-weight proteins revealed that the oligomer has an Mr of 500,000-550,000. This result clearly indicates that the native form of the type A receptor is a tetramer composed of four 140-kDa disulfide-linked receptor/cyclase molecules.
 ...
PMID:Bifunctional atrial natriuretic peptide receptor (type A) exists as a disulfide-linked tetramer in plasma membranes of bovine adrenal cortex. 165

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

In Dictyostelium, chemotaxis to folate during growth and cAMP during aggregation is controlled via cell surface receptors. To study the role of two G alpha proteins (G alpha 1 and G alpha 2) in these responses, we examined the physiological and biochemical effects of null mutations caused by antisense mutagenesis and gene disruptions. Disruption of G alpha 2 results in an aggregation-deficient phenotype and a loss of cAMP receptor-mediated functions, including activation of adenylate cyclase, guanylate cyclase, and gene expression and in a loss of GTP-mediated decrease in receptor affinity for cAMP, but it has no effect on chemotaxis to folate or folate activation of guanylate cyclase. These phenotypes can be rescued by a vector expressing G alpha 2, suggesting G alpha 2 is coupled to a cAMP receptor but not to folate receptors. Loss of G alpha 1 expression resulted in no visible growth or developmental phenotype, including cAMP- and folate-stimulated responses, suggesting G alpha 1 function is either not essential under standard laboratory conditions or is encoded by multiple genes. Availability of null mutations provides suitable genetic backgrounds for expressing mutant G alpha protein subunits which can then be used to examine the physiological roles of G alpha 1 and G alpha 2. Construction of these gene disruptions was facilitated by using the auxotrophic marker THY1, which allowed for selection of single-copy insertions into the genome.
 ...
PMID:Molecular genetic analysis of two G alpha protein subunits in Dictyostelium. 167 Jul 74

Guanylate cyclase is regulated by adenine nucleotides in membranes of intestinal mucosal cells. Basal guanylate cyclase was activated about twofold by adenine nucleotides. Activation was specific for adenine, as compared with the pyrimidine nucleotides UTP and CTP. In addition, enzyme activation was obtained in the presence of saturating concentrations of GTP, the substrate for guanylate cyclase. The most potent adenine nucleotide was the nonhydrolyzable analog of ATP, adenosine 5'-O-(3-thiotriphosphate). Adenine nucleotide activation was specific for the particulate form of guanylate cyclase, as compared with the soluble form. Also, adenine nucleotides potentiated the activation of guanylate cyclase by the heat-stable enterotoxin produced by Escherichia coli. Indeed, enzyme activation by adenine nucleotides and toxin was greater than the sum of individual activations by these agents. Adenine nucleotides regulate guanylate cyclase by increasing the maximum velocity of the enzyme without altering its affinity for substrate or its cooperativity. In addition to stimulating guanylate cyclase, adenine nucleotides decreased the specific binding of the heat-stable enterotoxin to receptors in intestinal membranes. The coordinated regulation of the toxin-receptor interaction and guanylate cyclase activity by a process utilizing nonhydrolyzable analogs of a purine nucleotide is similar to the mechanisms involved in the hormone regulation of adenylate cyclase by guanine nucleotide-binding proteins. These data suggest that an adenine nucleotide-dependent protein may couple the toxin-receptor interaction to the regulation of particulate guanylate cyclase in intestinal membranes.
 ...
PMID:Activation of particulate guanylate cyclase by Escherichia coli heat-stable enterotoxin is regulated by adenine nucleotides. 167 3

Guanylate cyclase from rod photoreceptors of amphibian (toad, Bufo marinus, and frog, Rana catesbeiana) and bovine retinas was solubilized and purified by a single chromatography step on a GTP-agarose column. Silver staining of purified amphibian enzymes in SDS/polyacrylamide gels disclosed a doublet band (110 and 115 kDa), while the bovine enzyme appeared as a singlet band (110 kDa). The identification of these guanylate cyclases was confirmed using three chromatography systems with the purified enzymes. Specific binding to Con A-Sepharose suggested that rod guanylate cyclase is a glycoprotein. Two-dimensional gel electrophoresis of purified toad, frog, and bovine enzymes resolved two, three, and five variants, respectively, that differed in isoelectric point. Two variants of toad guanylate cyclase showed differences in various characterizations. These data suggest multiple mechanisms for regulation of guanylate cyclase activity in vertebrate rod photoreceptors.
 ...
PMID:Polymorphism in purified guanylate cyclase from vertebrate rod photoreceptors. 167 87

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.
 ...
PMID:Cytochemical and biochemical observations on the alveolar guanylate cyclase of golden hamster lung. 167 93

Light activation of cyclic GMP hydrolysis in rod outer segments is mediated by a G-protein which is active in the GTP-bound form. Substitution of GTP with a nonhydrolyzable GTP analogue is thought to leave the G-protein in a persistently activated state, thereby prolonging the hydrolysis of cyclic GMP. Restoration of cyclic GMP concentration in the cell also depends upon GTP since it is the substrate for guanylate cyclase, but little is known about the effects of GTP analogues on this enzyme. We report here the effects of the analogues of GTP and ATP as inhibitors and substrates of rod disk membrane guanylate cyclase. The rate of cyclic GMP synthesis from GTP in rod disk membranes was about 50 pmol min-1 (nmol of rhodopsin)-1. Analogues of GTP and adenine nucleotides competitively inhibited the cyclase activity. The order of inhibition, with magnesium as metal cofactor, was ATP greater than GMP-PNP greater than AMP-PNP approximately GTP-gamma-S; with manganese, AMP-PNP was more inhibitory than GTP-gamma-S. The inhibition constants, with magnesium as cofactor, were 0.65-2.0 mM for GTP-gamma-S, 0.4-0.8 mM for GMP-PNP, 1.5-2.3 mM for AMP-PNP, and 0.07-0.2 mM for ATP. The fraction of cyclase activity inhibited by analogues was similar at 1 and 0.03 microM calcium. Besides inhibition of cyclase, the analogues also served as its substrates. GTP-gamma-S substituted GTP with about 85% efficiency while GMP-PNP and ATP were about 5 and 7% as efficient, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Interactions of nucleotide analogues with rod outer segment guanylate cyclase. 167 98

We examined the effects of sulfhydryl-reactive redox agents and of the apparent oxidation-reduction (redox) potential of the assay medium on enzyme activity and atrial natriuretic factor (ANF) binding properties of particular guanylate cyclase from bovine adrenal cortex. Redox potential was varied by addition of redox-reactive agents and quantified by electrochemical measurement. The modification of free SH groups by thiol-reactive agents had only a minor effect on ANF binding or on the extent of ANF-dependent enzyme stimulation whereas free thiol groups were essential for basal enzyme activity of ANF-sensitive particulate guanylate cyclase. Basal and ANF-stimulated particulate guanylate cyclase activity was modulated by exposure to different redox potential states. This modulation was different for the substrates Mg.GTP and Mn.GTP. The apparent redox potential had no influence on the extent of guanylate cyclase activation by ANF. Our results suggest that critical free thiol groups, which are sensitive to thiol-reactive redox agents, are involved in the catalytic, but not in the receptor function of ANF-sensitive particulate guanylate cyclase. These thiol groups could be the structural basis for the effects of redox events which modulate basal enzyme activity, but not activation by ANF.
 ...
PMID:Functional modulation of ANF-sensitive particulate guanylate cyclase by redox mechanisms. 167 81


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