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)

Recently, the peptides guanylin and uroguanylin were identified as endogenous ligands of the membrane-bound guanylate cyclase C (GC-C) that is mainly expressed in the intestinal epithelium. In the present study, bioactive guanylin and uroguanylin have been prepared by solid-phase methodology using Fmoc/HBTU chemistry. The two disulfide bonds with relative 1/3 and 2/4 connectivity have been introduced selectively by air oxidation of thiol groups and iodine treatment of Cys(Acm) residues. Using this strategy, several sequential derivatives were prepared. Temperature-dependent HPLC characterization of the bioactive products revealed that guanylin-related peptides exist as a mixture of two compounds. The isoforms are interconverted within approximately 90 min, which prevents their separate characterization. This effect was not detected for uroguanylin-like peptides. Synthetic peptides were tested for their potential to activate GC-C in cultured human colon carcinoma cells (T84), known to express high levels of GC-C. The results obtained show that both disulfide bonds are necessary for GC-C activation. The presence of the amino-terminally neighboring residues of Cys104 for guanylin and Cys100 for uroguanylin has been found to be essential for GC-C stimulation. Unexpectedly, a hybrid peptide obtained from substitution of the central tripeptide AYA of guanylin by the tripeptide VNV of uroguanylin was not bioactive.
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PMID:Synthesis, biological activity and isomerism of guanylate cyclase C-activating peptides guanylin and uroguanylin. 930 86

Although guanosine 3',5'-cyclic monophosphate (cGMP) acts as a relaxant second messenger, the regulation of intracellular cGMP has not been comprehensively studied in human airway smooth muscle. We studied the production of cGMP by cultured human airway smooth muscle cells (HASMC) after stimulation with activators of soluble guanylyl cyclase [sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP)] and particulate guanylyl cyclase [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and Escherichia coli heat stable enterotoxin (STa)]. cGMP was measured by enzyme-linked immunosorbent assay. Both SNP (10(-6) to 10(-3) M) and SNAP (10(-6) to 10(-3) M) caused concentration-dependent elevation of cGMP in the presence of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (10(-3) M), with cGMP increasing 6- and 15-fold in response to SNP and SNAP, respectively, at the highest concentration tested (10(-3) M). The increases in cGMP in response to SNP (5 x 10(-5) M) and SNAP (10(-5) M) were inhibited by hemoglobin (Hb; 5 x 10(-5) M), a nitric oxide scavenger, and methylene blue (MB; 5 x 10(-4) M), an inhibitor of guanylyl cyclase. cGMP accumulation after SNAP was abolished by both Hb and MB. The response to SNP was inhibited by 79% with Hb and was abolished with MB. ANP, BNP, and CNP (10(-9) to 10(-5) M) + phosphoramidon (10(-6) M) caused a concentration-dependent elevation in cGMP with an order of potency ANP > BNP > CNP. cGMP formation in the presence of the highest concentration of the most potent natriuretic peptide (10(-5) M ANP) was two- to threefold greater than with the highest concentration of SNAP. The increase in cGMP seen with natriuretic peptides was similar in the presence or absence of phosphoramidon, a neutral endopeptidase (NEP) inhibitor, suggesting that NEP is not playing a role in modulating the effect of natriuretic peptides in HASMC. STa (400 IU/ml) had no effect on cGMP levels. SNAP- and ANP-induced cGMP accumulation was increased by the selective type V PDE inhibitors SKF-96231 and zaprinast, suggesting that type V PDE is responsible for cGMP breakdown in HASMC. These results suggest that cultured HASMC contain both soluble and particulate guanylyl cyclases. The order of potency of the natriuretic peptides ANP > BNP > CNP suggests that type A particulate membrane-bound guanylate cyclase predominates.
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PMID:Regulation of cGMP by soluble and particulate guanylyl cyclases in cultured human airway smooth muscle. 935 56

Intracellular communication and transmission of messages for many hormones and free radicals occur after the hormones and free radicals bind to their receptors by enhancing the activity of guanylate cyclase, the enzyme that catalyzes the conversion of guanosine triphosphate to the intracellular messenger cyclic guanosine-3'-5' monophosphate (cyclic GMP). The guanylate cyclase-linked receptors exist intracellularly (ie, cytoplasmic) and in membrane-bound forms. Enhancement of guanylate cyclase by hormones or free radicals increases intracellular cyclic GMP, which closes cation channels in the kidney while activating cation channels in the retina and olfactory cilia, either directly or by cyclic GMP-dependent protein kinase. Cyclic GMP also has potent blood pressure lowering properties. Cyclic GMP promotes growth by increasing DNA, RNA, and protein synthesis. Overactivity of this system is observed in Traveler's diarrhea, whereas underactivity occurs in Chediak-Higashi syndrome in which lysosomal enzyme release and chemotaxis are defective and can be corrected in vitro by addition of cyclic GMP.
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PMID:Signal transduction: activation of the guanylate cyclase-cyclic guanosine-3'-5' monophosphate system by hormones and free radicals. 936 33

Almost three decades of research in the field of photoreceptor guanylate cyclases are discussed in this review. Primarily, it focuses on the members of membrane-bound guanylate cyclases found in the outer segments of vertebrate rods. These cyclases represent a new guanylate cyclase subfamily, termed ROS-GC, which distinguishes itself from the peptide receptor guanylate cyclase family that it is not extracellularly regulated. It is regulated, instead, by the intracellularly-generated Ca2+ signals. A remarkable feature of this regulation is that ROS-GC is a transduction switch for both the low and high Ca2+ signals. The low Ca2+ signal transduction pathway is linked to phototransduction, but the physiological relevance of the high Ca2+ signal transduction pathway is not yet clear; it may be linked to neuronal synaptic activity. The review is divided into eight sections. In Section I, the field of guanylate cyclase is introduced and the scope of the review is briefly explained; Section II covers a brief history of the investigations and ideas surrounding the discovery of rod guanylate cyclase. The first five subsections of Section III review the experimental efforts to quantify the guanylate cyclase activity of rods, including in vitro and in situ biochemistry, and also the work done since 1988 in which guanylate cyclase activity has been determined. In the remaining three subsections an analytical evaluation of the Ca2+ modulation of the rod guanylate cyclase activity related to phototransduction is presented. Section IV deals with the issues of a biochemical nature: isolation and purification, subcellular localization and functional properties of rod guanylate cyclase. Section V summarizes work on the cloning of the guanylate cyclases, analysis of their primary structures, and determination of their location with in situ hybridization. Section VI summarizes studies on the regulation of guanylate cyclases, with a focus on guanylate cyclases activating proteins. In Section VII, the evidence about the localization and functional role of guanylate cyclases in other retinal cells, especially in "on-bipolar" cells, in which guanylate cyclase most likely plays a critical role in electrical signaling, is discussed. The review concludes with Section VIII, with remarks about the future directions of research on retinal guanylate cyclases.
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PMID:Photoreceptor guanylate cyclases: a review. 941 88

Membrane-bound guanylyl cyclase (GC) is regulated by muscarinic receptors (mAChRs). Carbamylcholine (CC) induces a "dual" biological response on GC activity. Thus, an activation is observed at 0.1 nM and a maximal response at 1 nM CC. However, at higher agonist concentration (> 100 nM), there is an agonist-dependent inhibition of GC. This CC dual response is affected by 4-DAMP and HDD (M3 antagonists), which produce a right-shift of the CC curve; the maximal CC dose response with 4-DAMP is more potent than that with HDD. Moreover, AFDX-DS (an M2 antagonist) increases basal activity and decreases the agonist-dependent inhibition. Neither the CC response nor the CC maximal dose responses are affected by pirenzepine (PZ, M1 antagonist). The agonist-dependent stimulation of GC activity is inhibited by 4-DAMP showing a -log IC50 = 8.4 +/- 0.4, while AFDX116 DS poorly inhibits such activity with a -log IC50 = 5.0 +/- 0.2. The agonist-independent (basal) GC activity also was inhibited by 4-DAMP, in a dose-dependent manner, with an IC50 = 8.5 +/- 0.2. Nonetheless, other muscarinic antagonists (PZ and HDD) were not able to inhibit this basal GC. Pertussis toxin treatment produces a complete blockade of the agonist-dependent inhibition of GC with a full expression of the agonist-dependent activation of membrane-bound GC. These results indicate that membrane-bound GC is regulated by muscarinic agents through two opposite signaling pathways; one involves the activation of GC via an M3 mAchR coupled to a PTX-insensitive G protein, while the GC inhibition is mediated through a PTX-sensitive Gi/o protein possibly coupled to an M2 mAChR.
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PMID:Two opposite signal transducing mechanisms regulate a G-protein-coupled guanylyl cyclase. 946 15

Activation of the natriuretic peptide system lowers blood pressure and causes the excretion of salt. Atrial natriuretic peptide and B-type natriuretic peptide are the humoral mediators of this effect; they act primarily by binding to membrane-bound natriuretic peptide receptor A (NPRA) and stimulating its intrinsic guanylate cyclase activity. To study whether genetically determined differences in NPRA expression affect blood pressure we have generated mice with one, two, three, or four copies of the gene encoding NPRA (Npr1 in the mouse). Atrial natriuretic peptide-dependent guanylate cyclase activity ranged progressively from approximately one-half normal in one-copy animals to twice normal in four-copy animals (P < 0.001). On different diets (0.05%, 2%, and 8% NaCl), the blood pressures of F1 male mice having only one copy of Npr1 averaged 9.1 mmHg (1 mmHg = 133 Pa) above those of wild-type two-copy males (P < 0.001), whereas males with three copies of the gene had blood pressures averaging 5.2 mmHg below normal (P < 0.01). The blood pressures of the one-copy F1 animals were significantly higher (by 6.2 mmHg; P < 0.01) on the high-salt than on the low-salt diet. The blood pressures of four-copy F3 males were significantly lower (by 7 mmHg; P < 0.05) on the high-salt than on the low-salt diet. These results demonstrate that below normal Npr1 expression leads to a salt-sensitive increase in blood pressure, whereas above normal Npr1 expression lowers blood pressures and protects against high dietary salt.
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PMID:Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. 948 23

The cytosolic calcium level ([Ca2+]i) and the membrane-bound guanylyl cyclase activity in the isolated rat intestinal epithelial cells were investigated. Heat-stable enterotoxin of Vibrio cholerae non-01 (NAG-ST) was found to increase both the [Ca2+]i and the enzyme activity. These changes occur similarly until 5 min of incubation with NAG-ST, indicating that these changes might be involved in NAG-ST induced signal transduction in rat enterocytes.
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PMID:Rise of cytosolic Ca2+ and activation of membrane-bound guanylyl cyclase activity in rat enterocytes by heat-stable enterotoxin of Vibrio cholerae non-01. 949 23

The influence of arachidonic acid (AA) on the feedback regulation of mesangial contraction by large Ca(2+)-activated K+ channels (BKCa) was determined through single-channel analysis using the patch clamp method. The mesangial BKCa is a low-gain negative feedback inhibitor of contraction that is activated in response to agonist-induced Ca2+ transients and membrane depolarization. AA activated BKCa in cell-attached patches in a dose-dependent manner with a maximal effect at 400 nM and a half-maximal response at 49 nM. In inside-out patches, AA directly activated BKCa with a maximal effect at 400 nM. BKCa was activated significantly in response to addition of 100 nM ANG II in the presence but not the absence of AA. Since it was shown previously that fatty acids stimulated both soluble and membrane-bound guanylyl cyclase, we determined whether AA activated BKCa by interfering with cGMP-mediated signal transduction pathways. It was previously shown that 10 microM cGMP, via cGMP-dependent protein kinase, activated BKCa in a biphasic manner with an early increase in probability of a channel existing in an open state (Po) and a subsequent inactivation mediated by protein phosphatase 2A (PP2A). We found that 10 microM dibutyryl-cGMP enhanced BKCa activity in an additive manner with saturating concentrations (400 nM) of AA. Moreover, the inactivation phase mediated by PP2A was not abolished. Thus AA does not affect the phosphorylation/dephosphorylation regulatory cycle for BKCa. It is concluded that AA potentiates the ANG II feedback response of BKCa by a mechanism that is independent of the phosphorylation cycle.
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PMID:Arachidonic acid potentiates the feedback response of mesangial BKCa channels to angiotensin II. 957 88

Intracellular cyclic GMP concentration is known to change in response to a wide variety of agents, including hormones, neurotransmitters or light. In vertebrate photoreceptors, different membrane-bound guanylate cyclase isoforms are responsible for cGMP synthesis and thus directly involved in termination of light signalling via the phototransduction cascade and recovery of the dark state. We have characterized a 4.7 kb long cDNA for the canine retinal guanylate cyclase isoform E (cGC-E) predicting a polypeptide of 1109 amino acids. The genomic structure and the complete sequence of the canine GC-E gene, which consists of 20 exons and spans about 14.5 kb, has also been determined. Northern blot analysis showed that GC-E was expressed in the canine retina as a 4.7 and 6.1 kb large transcript. RT-PCR analysis also detected low expression in cerebrum (occipital lobe). We performed a sequence analysis of the cGC-E gene in animals of a Swedish Briard and Briard-Beagle dog kinship in which an inherited retinal dystrophy is segregating. Several intragenic DNA polymorphisms were identified and used for segregation analysis which excluded cGC-E as a candidate gene for this type of canine retinal dystrophy.
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PMID:Organization of the canine gene encoding the E isoform of retinal guanylate cyclase (cGC-E) and exclusion of its involvement in the inherited retinal dystrophy of the Swedish Briard and Briard-beagle dogs. 965 84

In recent years, nitric oxide (NO), a single but highly reactive molecule has become known as the central point of many researchs. NO is synthesized by the enzyme nitric oxide synthase (NOS) in mammals from the amino-acid L-arginine. The products of L-arginine oxidation by NOS are L-citrulline and NO. Nitric oxide has a very short half life, is lipid soluble, reacts easily with several enzymatic systems, and is produced by a wide amount of cells. At least, three kinds of enzymes NOS have been described: two of them are calcium-dependent and continuously present in select cells (constitutive NOS, cNOS). One cNOS isoform is present in the cytosol of neuronal cells, while the other isoform is present in membrane-bound form, in endothelial cells. cNOS produces small quantities of NO, following stimulation by specific agonist. NO produced by cNOS frequently mediates cellular communications and cellular signaling. A third isoform is calcium-independent, is not present in unstimulated cells, and produces large quantities of NO following stimulation of the appropriate cell with cytokines or LPS (inducible NOS, iNOS). NO is a mediator of both physiological and pathological process. It acts directly on its targets, one of them, maybe the most important, is the soluble guanylate cyclase, and produces a variety of biological effects, ranged from cytoprotection to cytotoxicity. An analysis of the biochemistry and physiology of NO is the focus of this review, together with its biological action and potential therapeutical implications.
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PMID:[Physiological and physiopathological aspects of nitric acid in mammalian tissues]. 970 23


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