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 activity of the atrial natriuretic peptide receptor (Npr1) is altered in spontaneously hypertensive rats (SHR) in relation to its mRNA levels, suggesting abnormal transcriptional control in hypertension. A single-stranded conformational polymorphism caused by a repetitive dinucleotide segment of 10 TA in BN-Lx and of 40 TA in SHR was localized at position -943 relative to the transcription start site of the Npr1 gene, downstream of a putative cGMP-regulatory region, and was the only sequence difference noted between the two strains. Transient transfections of -1520 to -920 Npr1 promoter-SV40-luciferase fusion vector showed that the construct from BN-Lx stimulated the SV40 promoter, whereas that from SHR slightly inhibited it. In contrast to the BN-Lx construct, the activity of the SHR fragment was refractory to downregulation by atrial natriuretic peptide. Genotype-phenotype correlation studies in recombinant inbred strains (RIS) derived from BN-Lx and SHR crosses revealed significant correlations of the TA repeat with basal guanylyl cyclase activity and Npr1 mRNA levels. The correlations were heightened by a locus on chromosome 10 containing the Ace gene. The highest basal guanylyl cyclase activity and Npr1 mRNA values were found in RIS with both genes (Npr1/Ace) of BN genotypes, whereas the lowest were recorded in RIS, with the SHR genotypes at both loci. This was inversely correlated with diastolic blood pressure in these strains. In conclusion, the longer TA repeat unit in the promoter of Npr1 of SHR, in tandem with a putative cGMP responsive element, regulates the transcription of the Npr1 gene with consequences on diastolic blood pressure.
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PMID:TA repeat variation, Npr1 expression, and blood pressure: impact of the Ace locus. 1251 24

Evidence from several rodent models has suggested that a reduction of either atrial natriuretic peptide or its receptor in the heart affects cardiac remodeling by promoting the onset of cardiac hypertrophy. The atrial natriuretic peptide receptor mediates signaling at least in part via the generation of intracellular cyclic GMP. To directly test whether accumulation of intracellular cyclic GMP conveys protection against cardiac hypertrophy, we engineered transgenic mice that overexpress a catalytic fragment of constitutively active guanylate cyclase domain of the atrial natriuretic peptide receptor in a cardiomyocyte-specific manner. Expression of the transgene increased the intracellular concentration of cyclic GMP specifically within cardiomyocytes and had no detectable effect on cardiac performance under basal conditions. However, expression of the transgene attenuated the effects of the pharmacologic hypertrophic agent isoproterenol on cardiac wall thickness and prevented the onset of the fetal gene expression program normally associated with cardiac hypertrophy. Likewise, expression of the transgene inhibited the hypertrophic effects of abdominal aortic constriction, since it abolished its effects on ventricular wall thickness and greatly attenuated its effects on cardiomyocyte size. Altogether, our results suggest that cyclic GMP is a cardioprotective agent against hypertrophy that acts via a direct local effect on cardiomyocytes.
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PMID:Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse hearts. 1450 Jul 7

Cardiac hypertrophy is associated with ventricular arrhythmias and sudden death. The molecular mechanisms that predispose the hypertrophied heart to arrhythmias are not well understood. In mice, deletion of the gene coding for the atrial natriuretic peptide receptor, guanylyl cyclase A (GC-A-/-), causes arterial hypertension, cardiac hypertrophy and sudden death. We used this mouse model to study molecular mechanisms of arrhythmias in the hypertrophied heart. Right and left ventricular monophasic action potential durations (APD) were recorded in isolated, Langendorff-perfused hearts during pacing from the right atrium and ventricle. The atrioventricular (AV) node was ablated to provoke bradycardia. Intracellular Ca(2+) transients were measured in isolated INDO-1 loaded ventricular myocytes. Cardiac expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was analyzed by western blotting. Polymorphic ventricular arrhythmias (pVT) occurred spontaneously after mechanical AV block in 20/45 hearts from 12-month-old GC-A-/- mice (P < 0.05), but neither in age-matched GC-A+/+ hearts nor in hearts from 3-month-old mice of either genotype. Triggered activity preceded pVT. APD were prolonged and systolic Ca(i)(2+) levels were increased in GC-A-/- hearts independently of age. In 12-month-old GC-A-/- hearts only, dispersion of APD and expression levels of CaMKII were increased. CaMKII expression was particularly increased in hearts with pVT. Direct inhibition of CaMKII activation by KN93 (0.5 or 2 microM) or inhibition of Ca(2+)/calmodulin-dependent activation of CaMKII by W-7 (25 microM) suppressed pVT in GC-A-/- hearts (P < 0.05) while prolonging APD. The combination of increased CaMKII activity and altered action potential characteristics facilitates ventricular arrhythmias in hypertrophic GC-A-/- hearts.
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PMID:Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice. 1513 64

The natriuretic peptide receptor guanylate cyclases are members of the membrane-bound guanylate cyclase family. Atrial natriuretic pepticle (ANP) stimulates guanylate cyclase A, which is predominantly expressed in the rat parotid gland. ATP is well known to increase ANP-stimulated guanylate cyclase, with Mg2+ as a cofactor. We investigated the regulation of guanylate cyclase activity in rat parotid membranes with Mn2+ as a cofactor, because enzyme activity was much higher with Mn2+ than with Mg2+. ANP (10(-7)M) stimulated guanylate cyclase activity to 120%-130% of the control level, and ATP (0.1-1.0 mM) depressed its activity, with or without ANP, to 70%-80% of the control. Enzyme activity was increased by the addition of phosphate (5-20 mM). In the presence of phosphate (5 mM), guanylate cyclase with and without ANP was maximally stimulated to 5- and 6.6-fold of the control, respectively. The net stimulation of guanylate cyclase by ANP was increased at ATP concentrations between 0.2 and 0.5 mM in the presence of phosphate (5 mM or 10 mM), but no change was observed in the absence of phosphate. Phosphate not only stimulated guanylate cyclase in the absence of ATP but altered the ATP regulation of ANP-stimulated guanylate cyclase. The stimulation of guanylate cyclase by phosphate may depend on a peculiarity of rat parotid membranes.
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PMID:Stimulation of guanylate cyclase in rat parotid membranes by phosphate. 1549 Feb 99

We have identified a GDAY motif in the C-terminal domain of guanylyl cyclase (guanylate cyclase)/NPRA (natriuretic peptide receptor A) sequence, which serves a dual role as an internalization signal and a recycling signal. To delineate the role of the GDAY motif in receptor internalization and sequestration, we mutated Gly920, Asp921 and Tyr923 to alanine residues (GDAY/AAAA) in the NPRA cDNA sequence. The cDNAs encoding wild-type and mutant receptors were transfected in HEK-293 cells (human embryonic kidney 293 cells). The internalization studies of ligand-receptor complexes revealed that endocytosis of 125I-ANP by HEK-293 cells expressing G920A, Y923A or GDAY/AAAA mutant receptor was decreased by almost 50% (P<0.001) when compared with cells expressing the wild-type receptor. However, the effect of D921A mutation on receptor internalization was minimal. Ligand-mediated down-regulation of G920A, Y923A and GDAY/AAAA mutant receptors was decreased by 35-40% when compared with wild-type NPRA. Subsequently, the recycling of internalized D921A and GDAY/AAAA mutant receptors from the intracellular pool was decreased by more than 40+/-4% when compared with wild-type NPRA. Recycling of G920A and Y923A mutant receptors was also decreased, but to a significantly lesser extent compared with the D921A or GDAY/AAAA mutant receptors. We conclude that the Gly920 and Tyr923 residues within the GDAY consensus motif are necessary for internalization, and that residue Asp921 is important for recycling of NPRA. The current results provide new evidence for a dual role of the GDAY sequence motif in ligand-mediated internalization, recycling and down-regulation of a single-transmembrane receptor protein NPRA.
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PMID:Internalization and trafficking of guanylyl (guanylate) cyclase/natriuretic peptide receptor A is regulated by an acidic tyrosine-based cytoplasmic motif GDAY. 1557 17

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are loop-shaped peptidic hormones that have multiple actions on body fluid homeostasis. Their physiological effects are mediated through the activation of their receptor, natriuretic peptide receptor A (NPRA). This receptor is a member of the membrane guanylyl cyclase family and catalyzes cyclic guanosine monophosphate (cGMP) production following its activation. To map the binding site of human NPRA, we applied the methionine proximity assay method to this receptor. We photolabeled NPRA mutants, presenting a single methionine in the binding domain of the receptor, and used benzoylphenylalanine- (Bpa-) substituted peptides at positions 0, 3, 18, 26, and 28 of the ligand. We identified that the N-terminus of the peptide is interacting with the region between Asp(177) and Val(183) of the receptor. Arg(3) is interacting in the vicinity of Phe(172). Leu(18) binds close to Val(116). Phe(26) binds in the vicinity of His(195), and the C-terminal Tyr(28) is located close to Met(173). We next proceeded with photolabeling of a dual Bpa-substituted peptide and showed that the N-terminus and Leu(18) interact with opposite receptor subunits. On the basis of our results, a molecular model of peptide-bound NPRA was developed by homology modeling with the C-type natriuretic peptide- (CNP-) bound natriuretic peptide receptor C (NPRC) crystal structure. The model has been validated by molecular dynamics simulations. Our work provides a rational basis for interpreting and predicting natriuretic peptide binding to the human NPRA.
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PMID:Photolabeling study of the ligand binding domain of natriuretic peptide receptor A: development of a model. 1570 52

Mice carrying a targeted disruption of the Npr1 gene (coding for guanylyl cyclase/natriuretic peptide receptor A (NPRA)) exhibit increased blood pressure, cardiac hypertrophy, and congestive heart failure, similar to untreated human hypertensive patients. The objective of this study was to determine whether permanent ablation of NPRA signaling in mice alters the expression of matrix metalloproteinase (MMP)-2 and MMP-9 and pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), leading to myocardial collagen remodeling. Here, we report that expression levels of the MMP-2 and MMP-9 genes were increased by 3-5-fold and that the expression of the TNF-alpha gene was enhanced by 8-fold in Npr1 homozygous null mutant (Npr1-/-) mouse hearts compared with wild-type (Npr1+/+) control mouse hearts. Myocardial fibrosis, total collagen, and the collagen type I/III ratio (p < 0.01) were dramatically increased in adult Npr1-/- mice compared with age-matched wild-type counterparts. Hypertrophic marker genes, including the beta-myosin heavy chain and transforming growth factor-beta1, were significantly up-regulated (3-5-fold) in both young and adult Npr1-/- mouse hearts. NF-kappa B binding activity in ventricular tissues was enhanced by 4-fold with increased translocation of the p65 subunit from the cytoplasmic to nuclear fraction in Npr1-/- mice. Our results show that reduced NPRA signaling activates MMP, transforming growth factor-beta1, and TNF-alpha expression in Npr1-/- mouse hearts. The findings of this study demonstrate that disruption of NPRA/cGMP signaling promotes hypertrophic growth and extracellular matrix remodeling, leading to the development of cardiac hypertrophy, myocardial fibrosis, and congestive heart failure.
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PMID:Involvement of the NF-kappa B/matrix metalloproteinase pathway in cardiac fibrosis of mice lacking guanylyl cyclase/natriuretic peptide receptor A. 1571 Jun 27

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide decrease blood pressure and cardiac hypertrophy by activating natriuretic peptide receptor A (NPR-A), a transmembrane guanylyl cyclase also known as guanylyl cyclase A. Inactivation of NPR-A is a potential mechanism for the renal hyporesponsiveness observed in congestive heart failure (CHF) but direct data supporting this hypothesis are lacking. We examined whether NPR-A activity was reduced in CHF, and if so, by what mechanism. In two separate trials, CHF was induced in mice by 8-wk transverse aortic constriction. Sham controls underwent surgery without constriction. The constricted animals developed severe heart failure as indicated by increased heart weight, increased left ventricular end diastolic and systolic diameters, and decreased left ventricular ejection fractions. Kidney membranes were assayed for guanylyl cyclase activity or used to purify NPR-A by sequential immunoprecipitation/SDS-PAGE. Maximal ANP-dependent guanylyl cyclase activities were reduced by 44 or 43% in kidney membranes from CHF animals in two independent trials. Basal cyclase activities were also reduced by 31% in the second trial. The amount of phosphorylated NPR-A was reduced by 25 or 24% in kidney membranes from CHF animals as well. SYPRO Ruby staining suggested that NPR-A protein levels were similar between treatments in the first trial. However, more accurate estimates of NPR-A protein levels by immunoprecipitation/Western analysis in the second trial indicated that NPR-A protein was reduced by 30%. We conclude that reduced NPR-A protein levels, not receptor dephosphorylation, explain the renal hyporesponsiveness to natriuretic peptides in CHF.
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PMID:Renal hyporesponsiveness to atrial natriuretic peptide in congestive heart failure results from reduced atrial natriuretic peptide receptor concentrations. 1726 12

The asteroidal sperm-activating peptides (asterosaps) from the egg jelly bind to their sperm receptor, a membrane-bound guanylate cyclase, on the tail to activate sperm in sea stars. Asterosaps are produced as single peptides and then cleaved into shorter peptides. Sperm activation is followed by the acrosome reaction, which is subfamily specific. In order to investigate the molecular details of the asterosap-receptor interaction, corresponding cDNAs have been cloned, sequenced and analysed from the Asteriinae subfamily including Asterias amurensis, A. rubens, A. forbesi and Aphelasterias japonica, as well as Distolasterias nipon from the Coscinasteriinae subfamily. Averages of 29% and 86% identity were found from the deduced amino acid sequences in asterosap and its receptor extracellular domains, respectively, across all species examined. The phylogenic tree topology for asterosap and its receptor was similar to that of the mitochondrial cytochrome c oxidase subunit I. In spite of a certain homology, the amino acid sequences exhibited speciation. Conservation was found in the asterosap residues involved in disulphide bonding and proteinase-cleaving sites. Conversely, similarities were detected between potential asterosap-binding sites and the structure of the atrial natriuretic peptide receptor. Although the sperm-activating peptide and its receptor share certain common sequences, they may serve as barriers that ensure speciation in the sea star A. amurensis and closely related species.
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PMID:Conserved sequences of sperm-activating peptide and its receptor throughout evolution, despite speciation in the sea star Asterias amurensis and closely related species. 1857 50

The intestinal guanylyl cyclase-C (GC-C) was originally identified as an Escherichia coli heat-stable enterotoxin (STa) receptor. STa stimulates GC-C to much higher activity than the endogenous ligands guanylin and uroguanylin, causing severe diarrhea. To investigate the interactions of the endogenous and bacterial ligands with GC-C, we designed and characterized a soluble and properly folded fragment of the extracellular ligand-binding domain of GC-C. The membrane-bound guanylyl cyclases exhibit a single transmembrane spanning helix and a globularly folded extracellular ligand-binding domain that comprises about 410 of 1050 residues. Based on the crystal structure of the dimerized-binding domain of the guanylyl cyclase-coupled atrial natriuretic peptide receptor and a secondary structure-guided sequence alignment, we generated a model of the extracellular domain of GC-C comprised of two subdomains. Mapping of mutational and cross-link data onto this structural model restricts the ligand-binding region to the membrane proximal subdomain. We thus designed miniGC-C, a 197 amino acid fragment that mimics the ligand-binding membrane proximal subdomain. Cloning, expression and spectroscopic studies reveal miniGC-C to be a soluble and properly folded protein with a distinct secondary and tertiary structure. MiniGC-C binds STa with nanomolar affinity.
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PMID:Design and characterization of a soluble fragment of the extracellular ligand-binding domain of the peptide hormone receptor guanylyl cyclase-C. 1898 30


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