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 guanylyl cyclase receptor family contains members that exist in both the particulate and soluble fractions of cell homogenates. Based on cloning studies, proteins with guanylyl cyclase activity contain a single transmembrane domain, or exist as heterodimers with no apparent transmembrane domains. The members containing the single transmembrane domain appear to act as cell surface receptors for peptides such as natriuretic peptides and bacterial heat-stable enterotoxins, while the heterodimeric forms are activated by nitric oxide. The concentrations of the intracellular messenger, cyclic GMP, then, are regulated by multiple primary signaling molecules, all of which appear to bind directly to the guanylyl cyclase enzyme.
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PMID:Guanylyl cyclase-linked receptors. 168 38

Recoverin, a new calcium binding protein from bovine rod photoreceptor cells, activates guanylyl cyclase below a free calcium concentration of 200 nM. We show here that recoverin is phosphorylated by an endogenous kinase and Mg-ATP at the same decreased calcium concentration. The calcium-dependent activation of guanylyl cyclase is enhanced in the presence of ATP. We suggest that phosphorylation of recoverin reinforces the stimulation of guanylyl cyclase at decreased calcium concentrations.
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PMID:Phosphorylation of recoverin, the calcium-sensitive activator of photoreceptor guanylyl cyclase. 168 52

We studied the biological activity, stability and interaction of dinitrosyl-iron(II)-L-cysteine with vascular tissue. Dinitrosyl-iron(II)-L-cysteine was a potent activator of purified soluble guanylyl cyclase (EC50 10 nM with and 100 nM without superoxide dismutase) and relaxed noradrenaline-precontracted segments of endothelium-denuded rabbit femoral artery (EC50 10 nM superoxide dismutase). Pre-incubation (5 min; 310 K) of endothelium-denuded rabbit aortic segments with dinitrosyl-iron(II)-L-cysteine (0.036-3.6 mM) resulted in a concentration-dependent formation of a dinitrosyl-iron(II) complex with protein thiol groups, as detected by ESR spectroscopy. While the complex with proteins was stable for 2 h at 310 K, dinitrosyl-iron(II)-L-cysteine in aqueous solution (36-360 microM) decomposed completely within 15 min, as indicated by disappearance of its isotropic ESR signal at gav = 2.03 (293 K). Aortic segments pre-incubated with dinitrosyl-iron(II)-L-cysteine released a labile vasodilating and guanylyl cyclase activating factor. Perfusion of these segments with N-acetyl-L-cysteine resulted in the generation of a low molecular weight dinitrosyl-iron(II)-dithiolate from the dinitrosyl-iron(II) complex with proteins, as revealed by the shape change of the ESR signal at 293 K. The low molecular weight dinitrosyl-iron(II)-dithiolate accounted for an enhanced guanylyl cyclase activation and vasodilation induced by the aortic effluent. We conclude that nitric oxide (NO) produced by, or acting on vascular cells can be stabilized and stored as a dinitrosyl-iron(II) complex with protein thiols, and can be released from cells in the form of a low molecular weight dinitrosyl-iron(II)-dithiolate by intra- and extracellular thiols.
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PMID:The potent vasodilating and guanylyl cyclase activating dinitrosyl-iron(II) complex is stored in a protein-bound form in vascular tissue and is released by thiols. 168 53

Plasma membrane forms of guanylyl cyclase have been shown to function as natriuretic peptide receptors. We describe a new clone (GC-C) encoding a guanylyl cyclase receptor for heat-stable enterotoxin. GC-C encodes a protein containing an extracellular amino acid sequence divergent from that of previously cloned guanylyl cyclases; however, the protein retains the intracellular protein kinase-like and cyclase catalytic domains. Expression of GC-C in COS-7 cells results in high guanylyl cyclase activity. In addition, heat-stable enterotoxin from E. coli, but not natriuretic peptides, causes marked elevations of cyclic GMP and is specifically bound by cells transfected with GC-C. The enterotoxin fails to elevate cyclic GMP in nontransfected cells or in cells transfected with the natriuretic peptide/guanylyl cyclase receptors. These results show that a heat-stable enterotoxin receptor responsible for acute diarrhea is a plasma membrane form of guanylyl cyclase.
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PMID:Guanylyl cyclase is a heat-stable enterotoxin receptor. 170 94

L-Arginine-derived nitric oxide acts as an inter- and intracellular signal molecule with cytosolic guanylyl cyclase as the effector system. Two NO synthase isoenzymes are postulated: a cytokine-inducible enzyme in macrophages and a constitutive, Ca2(+)-regulated enzyme in various other cells. An NO synthase was isolated from porcine cerebellum by ammonium sulfate precipitation and affinity chromatography on 2',5'-ADP-Sepharose. The enzyme was identified as an NO synthase with a specific NO-chemiluminescence method and with purified cytosolic guanylyl cyclase as an NO-sensitive detection system. The purified NO synthase was, besides Ca2+/calmodulin and NADPH, largely dependent on tetrahydrobiopterin as a cofactor.
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PMID:Purification of a Ca2+/calmodulin-dependent nitric oxide synthase from porcine cerebellum. Cofactor-role of tetrahydrobiopterin. 170 32

The soluble form of guanylyl cyclase-activating-factor (GAF) synthase from rat cerebellum was purified to homogeneity by sequential affinity chromatographic steps on adenosine 2',5'-bisphosphate (2',5'-ADP)-Sepharose and calmodulin-agarose. Enzyme activity during purification was bioassayed by the L-arginine-, NADPH-, and Ca2+/calmodulin-dependent formation of a plasma membrane-permeable nitric oxide-like factor that stimulated soluble guanylyl cyclase in RFL-6 cells. With calmodulin and NADPH as cofactors, purified soluble GAF synthase induced an increase of 1.05 mumol of cGMP per 10(6) RFL-6 cells per 3 min per mg of protein. The coproduct of this signal-transduction pathway appeared to be L-citrulline. GAF synthase catalyzed the conversion of 107 nmol of L-arginine into L-citrulline per min per mg of protein. Based on these assays, this represents a purification of GAF synthase of approximately 10,076- and 8925-fold with recoveries of 16% and 19%, respectively. Rechromatography of the purified enzyme on Mono P (isoelectric point = 6.1 +/- 0.3), Mono Q, and Superose 12 or 6 resulted in no further purification or increase in specific activity. A Stokes radius of 7.9 +/- 0.3 nm and a sedimentation coefficient s20,w of 7.8 +/- 0.2 S were used to calculate a molecular mass of about 279 +/- 25 kDa for the native enzyme. SDS/PAGE revealed a single protein band with a molecular mass of about 155 +/- 3 kDa. These data suggest that soluble GAF synthase purified from rat cerebellum is a homodimer of 155-kDa subunits and that enzyme activity is dependent upon the presence of calmodulin.
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PMID:Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase. 170 96

NADPH diaphorase histochemistry selectively labels a number of discrete populations of neurons throughout the nervous system. This simple and robust technique has been used in a great many experimental and neuropathological studies; however, the function of this enzyme has remained a matter of speculation. We, therefore, undertook to characterize this enzyme biochemically. With biochemical and immunochemical assays, NADPH diaphorase was purified to apparent homogeneity from rat brain by affinity chromatography and anion-exchange HPLC. Western (immunoblot) transfer and immunostaining with an antibody specific for NADPH diaphorase labeled a single protein of 150 kDa. Nitric oxide synthase was recently shown to be a 150-kDa, NADPH-dependent enzyme in brain. It is responsible for the calcium/calmodulin-dependent synthesis of the guanylyl cyclase activator nitric oxide from L-arginine. We have found that nitric oxide synthase activity and NADPH diaphorase copurify to homogeneity and that both activities could be immunoprecipitated with an antibody recognizing neuronal NADPH diaphorase. Furthermore, nitric oxide synthase was competitively inhibited by the NADPH diaphorase substrate, nitro blue tetrazolium. Thus, neuronal NADPH diaphorase is a nitric oxide synthase, and NADPH diaphorase histochemistry, therefore, provides a specific histochemical marker for neurons producing nitric oxide.
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PMID:Neuronal NADPH diaphorase is a nitric oxide synthase. 170 73

Microlocalization of mRNA coding for the guanylyl cyclase-coupled atrial natriuretic factor (ANF) receptor was carried out in the rat kidney. We used a combination of reverse transcription and polymerase chain reaction (RT-PCR) in individual microdissected renal tubule segments, glomeruli, and vasa recta bundles. Relative quantitation of the resulting amplified cDNA utilized densitometry of autoradiograms from Southern blots probed with a specific 32P-labeled probe. Among renal tubule segments, the largest signal was found in the terminal inner medullary collecting duct (IMCD). Slightly smaller signals were found in the initial IMCD and in loop of Henle segments from the inner medulla. Readily detectable signals were also seen in the following segments (in descending order): cortical collecting duct, proximal convoluted tubule, medullary thick ascending limb, cortical thick ascending limb, distal convoluted tubule, and outer medullary collecting duct. Large signals were also detected in glomeruli and in vasa recta bundles from the inner stripe of the outer medulla. Based on these results, we conclude that 1) renal microlocalization of specific mRNAs coding for hormone receptors is feasible through application of the RT-PCR procedure in microdissected renal tubules and vascular elements, and 2) the gene for the guanylyl cyclase-coupled ANF receptor is broadly expressed along the nephron, raising the possibility that multiple sites of ANF action are present.
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PMID:RT-PCR microlocalization of mRNA for guanylyl cyclase-coupled ANF receptor in rat kidney. 172 96

A survey of the available literature leads to the conclusion that the most probable mechanism by which nitrovasodilators act, is by nitric oxide (NO) formation. This by itself or by formation of a nitrosothiol (e.g. nitroscocysteine) activates guanylyl cyclase which increases the production of cyclic guanosine monophosphate (cGMP). Endothelium-derived relaxing factor (EDRF), which later turned out to be or to form NO, relaxes smooth muscle by stimulating cGMP formation. The effect of cGMP is mediated by a cGMP-dependent protein kinase and causes a reduction in the intracellular concentration of free Ca2+ ions in the smooth muscle cell. The precise mechanism of this effect is not completely clear but sequestration into sarcoplasmatic reticulum seems to play a major role. In order to identify the nature of the endogenous stimulator of guanylyl cyclase, i.e. to decide whether it is a nitrosothiol or the free radical NO, we compared the effects of NO, nitrosocysteine and nitrosoglutathione on vascular relaxation and increases in cGMP levels in isolated bovine circular strips and on guanylyl cyclase activity in vitro. Induction of tolerance and of cross-tolerance between various NO donors was also investigated. Nitrosodium and nitrosoglutathione augmented cGMP and relaxed vascular smooth muscle slightly more powerfully than NO. The three agents induced slight tolerance after repeated administration without affecting cGMP rises or desensitizing guanylyl cyclase. Pretreatment of coronary strips with nitrosoglutathione caused largely similar cross-tolerance as did NO against nitroglycerin, SIN-1 and sodium nitroprusside. The similarities to NO characterize nitrosocysteine as its most likely precursor, e.g. as EDRF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular mechanisms of action of therapeutic nitric oxide donors. 179 Jul 79

Angiotensin II (Ang II) receptors, estimated by the specific binding of the peptide Ang II receptor antagonist [125I] [Sar1,Ile8]Ang II, are localized on multiple ovarian structures, including follicular granulosa cells. Using the Ang II receptor subtype-selective nonpeptide antagonists, DuP 753 [selective for the type 1 Ang II (AT1) receptor] and PD 123319 [selective for the type 2 Ang II (AT2) receptor], we show that follicular granulosa cells, in vivo and in vitro, exclusively express the AT2 receptor. To understand the function of Ang II in ovarian follicles, we compared the biochemical properties and transmembrane signaling pathways of the granulosa cell AT2 receptor with those properties generally associated with Ang II receptors found in the adrenal zona glomerulosa, where the AT1 receptor predominates. The mol wt of the granulosa cell AT2 receptor (approximately 79,000), estimated by affinity cross-linking studies, is similar to that of the adrenal zona glomerulosa Ang II receptor. Like the adrenal zona glomerulosa Ang II receptor, binding inhibition studies show that the granulosa cell AT2 receptor binds Ang II and Ang III with high affinity (IC50, approximately 0.5 nM for both peptides), but not Ang-(1-7) (IC50, approximately 0.5 microM) or Ang-(1-5) (IC50, greater than 10 microM). However, unlike the adrenal zona glomerulosa Ang II receptor, the granulosa cell AT2 receptor does not undergo agonist-induced endocytosis. Further, Ang II does not affect basal or stimulated inositol phosphate production, intracellular Ca2+ mobilization, or adenylyl cyclase or guanylyl cyclase activity in granulosa cells. The granulosa cell AT2 receptor does not appear to directly interact with guanine nucleotide binding regulatory proteins, since agonist dissociation from the AT2 receptor is unaffected by the GTP analog guanosine 5'-O-(3-thiotriphosphate); in contrast, the AT1 receptor appears to directly interact with guanine nucleotide binding regulatory protein, because agonist dissociation from the AT1 receptor is stimulated by guanosine 5'-O-(3-thiotriphosphate). These studies clearly demonstrate that the granulosa cell AT2 receptor is functionally distinct from the well characterized adrenal zona glomerulosa Ang II receptor. The exclusive presence of the AT2 receptor on the granulosa cell makes it an ideal cell type for studying the potential, but as yet unknown, function of this receptor.
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PMID:Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor. 184 6


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