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)

Autoradiography of frozen sections of fetal rat brain shows that receptor-like binding sites for atrial and C-type natriuretic peptides (ANP and CNP) occur in the generative juxtaventricular zone of the telencephalon after the 12th embryonic day (E12). These sites avidly bind both ANP and CNP. They thus resemble the cloned NPR-C type of natriuretic peptide receptor. Covalent cross-linking of 3-[125I]iodo-O-tyrosyl CNP-(1-22) and 3-[125I]iodo-28-tyrosyl rat ANP-(1-28) to membrane proteins from E16 telencephala labels a single protein band on reducing sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The protein has high affinities for ANP and CNP and a molecular mass of 60-70 kDa under reducing conditions, consistent with reduced NPR-C. However, because the telencephalic protein has unusual physicochemical properties in SDS under nonreducing conditions it was not possible to assess whether this protein can form disulfide-bridged dimers like NPR-C. CNP-(1-22) was a full agonist and ANP-(1-28) was a partial agonist of guanosine 3',5'-cyclic monophosphate (cGMP) production by E16 telencephalon. C-ANP, a synthetic ligand of NPR-C, antagonized CNP-(1-22)-mediated cGMP production. The results imply that either the NPR-C-like telencephalic receptor modulates the level of cGMP or a guanylate cyclase-coupled receptor, such as the 120-kDa B-type NPR, for which CNP-(1-22) is a full agonist, is present at levels insufficient to be detected by autoradiography or protein labeling.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Natriuretic peptide receptors are expressed during cerebral growth in the fetal rat. 765 46

In bovine lung membranes, atrial natriuretic peptide (ANP) showed temperature-dependent binding to guanylate cyclase-natriuretic peptide receptor (NPR-GC). Photoaffinity labeling of the receptors with 4-azidobenzoyl (AZB)-125I-ANP and competitive binding studies with 125I-ANP, ANP, and atriopeptin I (API) revealed that NPR-GC was detected as the predominant ANP-binding protein at 0 degrees C, whereas at 37 degrees C natriuretic peptide clearance receptor (NPR-C) was detected as the predominant protein. The ratio of NPR-GC and NPR-C was 89:11 at 0 degrees C for 40 min, respectively, whereas 6:94 at 37 degrees C. AZB-125I-ANP bound to NPR-GC dissociated from the binding site within 5 min at 37 degrees C but not at 0 degrees C, whereas ANP bound to NPR-C did not dissociate from the binding site at 0 and 37 degrees C. The dissociated AZB-125I-ANP rapidly rebound to NPR-GC at 37 degrees C but not to NPR-C, and the dissociated NPR-GC was capable of binding. Some AZB-125I-ANP was hydrolyzed by a membrane-bound proteinase(s). Phosphoramidon inhibited the hydrolysis of AZB-125I-ANP. Thus, the dissociated AZB-125I-ANP rebound to NPR-GC and NPR-C. These results suggest that usually intact ANP repeatedly binds to NPR-GC until hydrolysis. Furthermore, the majority of ANP bind to NPR-GC before binding to NPR-C under physiological temperature.
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PMID:Interaction of atrial natriuretic peptide with its receptors in bovine lung membranes. 770 15

The natriuretic peptide receptor-C (NPR-C) constitutes greater than 95% of the natriuretic peptide binding sites in vivo. This cell surface glycoprotein is a disulfide-linked homodimer with a subunit molecular weight of 68,000. Two sources and types of ANP affinity-purified human NPR-C were used to map disulfide linkages and glycosylation sites of this receptor by mass spectrometry: the extracellular domain obtained by papain cleavage of a receptor-IgG fusion protein expressed in Chinese hamster ovary cells, and a baculovirus/Sf9-expressed cytoplasmic truncation mutant in which 34 of 37 cytoplasmic domain amino acids were deleted. Two intramolecular disulfide bonded loops were found in the 435 amino acid extracellular domain (C63-C91, C168-C216). The juxtamembrane residues C428 and C431 are involved in homodimer formation, confirmed by site-directed mutagenesis of full-length NPR. Three of the four potential Asn-linked glycosylation sites are occupied: N41 (complex), N248 (high mannose), and N349 (complex; partial occupancy). These data describe the intra- and intermolecular linkages in NPR-C, providing a model for the homologous guanylyl cyclase receptors, NPR-A and NPR-B; both of the cyclase receptors likely contain the first amino-terminal 29 amino acid loop, but only NPR-A possesses the second 49 amino acid loop in common with NPR-C.
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PMID:The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer. 772 88

The natriuretic peptide system comprises at least three endogenous ligands, namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and three receptors for natriuretic peptides (NPR), that is, NPR-A, NPR-B and clearance receptor (NPR-C). Three natriuretic peptides derived from the distinct genes share a common ring structure with 17 amino acids formed by a disulfide linkage which confers the unique biological property on these peptides. ANP and BNP are elucidated to be the cardiac hormone mainly secreted from the atrium, and from the ventricle, respectively. CNP, first recognized as the neuropeptide, is now identified within the vascular wall, especially in endothelial cells and considered to be the peptidic endothelium-derived relaxing factor (EDRF). While NPR-A shows the high affinity to ANP and BNP, NPR-B is the selective receptor for CNP. These two types of "biologically active" NPR are the membrane-bound guanylate cyclase itself, and mediate the wide range of biological actions of natriuretic peptides through cyclic GMP-dependent cascade. The clearance receptor shows the ligand-binding affinity with the rank order of ANP > CNP > BNP and is considered to be involved in the clearance of the peptides. The natriuretic peptide system as an endocrine and paracrine/autocrine system serves as one of the key modulatory systems for blood pressure, body fluid homeostasis and vascular remodeling.
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PMID:[Molecular biology and pharmacology of natriuretic peptide system]. 810 May 90

These studies were designed to characterize the atrial natriuretic peptide (ANF) receptor subtypes [guanylyl cyclase natriuretic peptide receptors (NPR-A, NPR-B) and NPR-C] in lungs of normal hamsters and to evaluate alterations in receptor kinetics in genetic cardiomyopathy (CMO), a model of human congestive heart failure. Lung membranes were obtained from normal and CMO 200-to 230-day-old hamsters. Cross-linking and competitive binding receptor assays using 125I-labeled human ANF showed that lung membranes exhibit NPR, mainly guanylyl cyclase NPR-A and clearance NPR-C receptors. Stimulation of guanylyl cyclase by ANF and C-type natriuretic peptide (CNP) confirmed the presence of NPR-A and NPR-B. The maximum binding capacity of total ANF binding sites (442 +/- 68 vs. 271 +/- 57 fmol/mg protein, P < 0.05) was reduced, but dissociation constant (0.26 +/- 0.04 vs. 0.41 +/- 0.08 nM) was not altered in CMO animals. Similar reductions were observed in the binding sites for brain natriuretic peptide (BNP; 438 +/- 83 vs. 236 +/- 53 fmol/mg protein) and CNP (321 +/- 80 vs. 165 +/- 56 fmol/mg protein, P < 0.05) which may reflect a decline in NPR-A and NPR-B and/or NPR-C. Acid wash improved binding of 125I-labeled rat ANF to lung membranes of both normal and CMO hamsters, but the tendency towards reduced binding in CMO hamsters did not reach statistical significance, implying that downregulation may not have been due only to prior occupancy of the receptors. Transcripts of NPR-A, NPR-B, and NPR-C receptors in hamster lungs were detected by quantitative polymerase chain reaction. Compared with normal controls, the CMO hamster lung NPR-A mRNA was reduced by 50%, but NPR-B mRNA and NPR-C mRNA were not altered. Moreover, CMO hamster lungs showed less activation of guanylyl cyclase by ANF. These studies demonstrate that lung NPR are downregulated in hamster CMO.
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PMID:Alteration of lung atrial natriuretic peptide receptors in genetic cardiomyopathy. 876 Jan 30

The receptor for atrial natriuretic peptide (ANP) is a type-I transmembrane protein containing an extracellular ligand-binding domain, a single transmembrane sequence, an intracellular kinase-homologous domain, and a guanylate cyclase (GCase) domain. Binding of ANP to the extracellular domain causes activation of the GCase domain by an as yet unknown mechanism. To facilitate studies of the receptor structure and signaling mechanism, we have expressed the extracellular ANP-binding domain of rat ANP receptor (NPR-ECD) in a water-soluble form. NPR-ECD was purified to homogeneity by ANP-affinity chromatography. SDS-PAGE gave a single 61-kDa band, which coincided with a radioactive band obtained by photoaffinity-labeling with N4alpha-azidobenzoyl-125I-ANP(4-28). Edman degradation gave a single amino-terminal sequence expected for the mature protein. Both trifluoromethanesulfonic acid and peptide-N-glycosidase F treatments yielded a 50-kDa band, indicating N-glycosylation. The molecular mass of 57 725 Da determined by mass spectrometry indicates the carbohydrate content at 16%. NPR-ECD bound ANP with an affinity comparable to that of the full-length receptor. The ligand selectivity of NPR-ECD (in the order ANP > brain natriuretic peptide >> C-type natriuretic peptide) was also similar to that of the full-length receptor. HPLC gel filtration of NPR-ECD gave a peak with an apparent mass of 74 kDa. Preincubation with ANP generated a new 150-kDa peak with a concomitant decrease of the 74-kDa peak. This shift in peak positions was ANP concentration-dependent and was complete at the NPR-ECD-to-ANP molar ratio of 1:1, indicating equimolar binding. The change in the apparent native molecular weight from 74 to 150 kDa suggests that binding causes dimerization of the NPR-ECD:ANP complex to yield an [NPR-ECD:ANP]2 complex.
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PMID:Expression and purification of the extracellular ligand-binding domain of the atrial natriuretic peptide (ANP) receptor: monovalent binding with ANP induces 2:2 complexes. 988 90

Natriuretic peptide receptor-A (NPR-A), a particulate guanylyl cyclase receptor, is composed of an extracellular domain (ECD) with a ligand binding site, a transmembrane spanning, a kinase homology domain (KHD), and a guanylyl cyclase domain. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), the natural agonists, bind and activate the receptor leading to cyclic GMP production. This receptor has been reported to be spontaneously dimeric or oligomeric. In response to agonists, the KHD-mediated guanylate cyclase repression is removed, and it is assumed that ATP binds to the KHD. Since NPR-A displays a pair of juxtamembrane cysteines separated by 8 residues, we hypothesized that the removal of one of those cysteines would leave the other unpaired and reactive, thus susceptible to form an interchain disulfide bridge and to favor the dimeric interactions. Here we show that NPR-AC423S mutant, expressed mainly as a covalent dimer, increases the affinity of pBNP for this receptor by enhancing a high affinity binding component. Dimerization primarily depends on ECD since a secreted NPR-A C423S soluble ectodomain (ECDC423S) also documents a covalent dimer. ANP binding to the unmutated ECD yields up to 80-fold affinity loss as compared with the membrane receptor. However, the ECD C423S mutation restores a high binding affinity. Furthermore, C423S mutation leads to cellular constitutive activation (20-40-fold) of basal catalytic production of cyclic GMP by the full-length mutant. In vitro particulate guanylyl cyclase assays demonstrate that NPR-AC423S displays an increased sensitivity to ATP treatment alone and that the effect of ANP + ATP joint treatment is cumulative instead of synergistic. Finally, the cellular and particulate guanylyl cyclase assays indicate that the receptor is desensitized to agonist stimulation. We conclude the following: 1) dimers are functional units of NPR-A guanylyl cyclase activation; and 2) agonists are inducing dimeric contact of the juxtamembranous region leading to the removal of the KHD-mediated guanylyl cyclase repression, hence allowing catalytic activation.
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PMID:A disulfide-bridged mutant of natriuretic peptide receptor-A displays constitutive activity. Role of receptor dimerization in signal transduction. 1009 64

The location and characteristics of atrial natriuretic peptide binding sites in the kidney of the toad, Bufo marinus, were determined. Specific (125)I-rANP binding sites were observed on glomeruli and blood vessels, but little if any binding was observed over regions corresponding to the renal tubules. (125)I-rANP binding in tissue sections and/or isolated membranes was completely displaced in the presence of 1 microM rat ANP, frog ANP, and porcine C-type natriuretic peptide (membranes only); however, residual binding remained after incubation with 1 microM of the NPR-C ligand, C-ANF, indicating the presence of two distinct binding sites. Electrophoresis of kidney membranes cross-linked to (125)I-rANP identified specific bands at approximately 70 and 140 kDa which correspond to the monomeric mass of NPR-C and the guanylate cyclase receptors, respectively. In addition, rat ANP, frog ANP, and porcine CNP stimulated a significant increase in cGMP production rates in membrane preparations, while C-ANF had no stimulatory effect. Two partial cDNA clones generated using primers based on conserved regions of vertebrate natriuretic peptide receptors showed high homology to an NPR-C and the natriuretic peptide guanylate cyclase receptors (NPR-GC), respectively. This study provides evidence that the kidney of B. marinus contains both NPR-C and NPR-GC and that the glomerulus is potentially the principal site of ANP regulation in the kidneys.
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PMID:Distribution and characterization of natriuretic peptide receptors in the kidney of the toad, Bufo marinus. 1041 38

The natriuretic peptide (NP) system consists of three types of hormones [atrial NP (ANP), brain or B-type NP (BNP), and C-type NP (CNP)] and three types of receptors [NP receptor (R)-A, NPR-B, and NPR-C]. ANP and BNP are circulating hormones secreted from the heart, whereas CNP is basically a neuropeptide. NPR-A and NPR-B are membrane-bound guanylyl cyclases, whereas NPR-C is assumed to function as a clearance-type receptor. ANP, BNP, and CNP occur commonly in all tetrapods, but ventricular NP replaces BNP in teleost fish. In elasmobranchs, only CNP is found, even in the heart, suggesting that CNP is an ancestral form. A new guanylyl cyclase-uncoupled receptor named NPR-D has been identified in the eel in addition to NPR-A, -B, and -C. The NP system plays pivotal roles in cardiovascular and body fluid homeostasis. ANP is secreted in response to an increase in blood volume and acts on various organs to decrease both water and Na+, resulting in restoration of blood volume. In the eel, however, ANP is secreted in response to an increase in plasma osmolality and decreases Na+ specifically, thereby promoting seawater adaptation. Therefore, it seems that the family of NPs were originally Na(+)-extruding hormones in fishes; however, they evolved to be volume-depleting hormones promoting the excretion of both Na+ and water in tetrapods in which both are always regulated in the same direction. Vertebrates expanded their habitats from fresh water to the sea or to land during evolution. The structure and function of osmoregulatory hormones have also undergone evolution during this ecological evolution. Thus, a comparative approach to the study of the NP family affords new insights into the essential function of this osmoregulatory hormone.
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PMID:Structural and functional evolution of the natriuretic peptide system in vertebrates. 1049 24

Natriuretic peptide (NP) receptors (NPRs) located at the endocardial endothelium are suggested to be involved in regulating myocardial contractility. However, the characteristics and modulation of NPRs in relation to cardiac failure are not well defined. This study examined the properties of NPRs in ventricular endocardium using quantitative receptor autoradiography, RT-PCR, Southern blot analysis, and activation of particulate guanylyl cyclase (GC) by NPs. In control rats, specific 125I-labeled rat atrial NP (rANP)(1-28) binding sites were localized in right (RV) and left ventricular (LV) endocardium. Binding affinities of 125I-rANP(1-28) were remarkably higher in RV than LV endocardium. Radioligand binding at these sites was mostly inhibited by des[Gln18,Ser19,Gly20,Leu21, Gly22]ANP(4-23), a specific NP clearance receptor ligand. mRNAs for all three recognized NPRs were detected in endocardial cells by RT-PCR and confirmed by Southern blot analysis. Production of cGMP by particulate GC in endocardial cell membranes was stimulated by NPs with a rank order of potency of C-type NP(1-22) >> brain NP (BNP)(1-26) > ANP(1-28). We also examined the modulation of these NPRs during cardiac hypertrophy induced by monocrotaline (MCT). In MCT-treated rats with pulmonary hypertension, specific (125)I-rANP(1-28) binding to hypertrophied RV endocardium almost disappeared and cGMP production by NPs was significantly decreased. In rats with pulmonary hypertension, plasma levels of ANP and BNP were increased by fivefold compared with controls. The results indicate that there is a differential distribution of NPRs in the cardiac chambers, with the most abundant binding sites in RV endocardium, that NPR-B is the predominant GC-coupled NPR in ventricular endocardium, and that endocardial NPRs are downregulated with ventricular hypertrophy. Downregulation of NPRs may be associated with an increment of endogenous NP production caused by mechanical overload in hypertrophied ventricle.
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PMID:Modulation of endocardial natriuretic peptide receptors in right ventricular hypertrophy. 1060 Aug 47


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