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)

In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP-/- mice). We observed focal fibrotic lesions in ventricles from BNP-/- mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-beta3, and pro-alpha1(I) collagen [Col alpha1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.
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PMID:Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart. 1155 81

C-type natriuretic peptide (CNP) is mainly distributed in the brain and vascular endothelium and is considered to act as a local regulator in many tissues. The present study was aimed to determine the presence of CNP system and its biological function in rabbit colon. The serial dilution curves of tissue extracts were parallel to the standard curve of CNP-22. With gel permeation chromatography and reverse-phase HPLC, the major immunoreactive peak of CNP was observed at the same elution time corresponding to the synthetic CNP-53. The concentration of CNP in the mucosal layer of colon was 212.49 +/- 30.44 pg/g tissue wet weight (n = 7), which was significantly higher than that in the muscular layer. The presence of CNP mRNA was also detected by RT-PCR and Southern blot analysis. Production of cGMP by the activation of particulate guanylyl cyclase stimulated by BNP and CNP was higher in membranes obtained from the muscular layer than from mucosal layer. More cGMP was produced by CNP than by ANP. Both natriuretic peptide receptor-A and -B mRNAs were detected by RT-PCR and specific binding sites to 125I-[Tyr(0)]-CNP-22 were mainly localized to the muscular layer. Synthetic CNP inhibited basal tension, frequency and amplitude of basal motility of taenia coli of the right colon. This study showing the presence of CNP system and its biological function in colon suggests that endogenous CNP synthesized in the mucosal layer may have a paracrine function as a local regulator of colonic motility.
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PMID:C-type natriuretic peptide system in rabbit colon. 1178 91

The present study was aimed at investigating whether the regulation of the local natriuretic peptide system is altered in the kidney and the vasculature in obstructive uropathy. Male Sprague-Dawley rats were bilaterally obstructed by ligation of the proximal ureters for 48 h. Control rats were treated in the same way, except that no ligature was made. The mRNA expression of the various isoforms of atrial, brain, and C-type natriuretic peptide (ANP, BNP, CNP) and different subtypes of natriuretic peptide receptor-A, -B, and -C (NPR-A, NPR-B, NPR-C) was determined in the kidney and the thoracic aorta by reverse transcription-polymerase chain reaction. The basal and stimulated activities of particulate guanylyl cyclase were also examined. Following the bilateral ureteral obstruction, the expression of ANP, BNP, and CNP was increased in the aorta as well as in the kidney. Contrary to this, the expression of NPR-A, NPR-B, and NPR-C was decreased both in the kidney and the aorta. Accordingly, the guanylyl cyclase activity was significantly decreased in response to natriuretic peptides. ANP relaxed phenylephrine-precontracted aortic rings in a dose-dependent manner, the degree of which was significantly diminished. Our results suggest that the local synthesis of natriuretic peptides is increased in the kidney and in the vasculature in obstructive uropathy.
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PMID:Local renal and vascular natriuretic peptide system in obstructive uropathic rats. 1208 22

A novel membrane guanylyl cyclase (membrane GC), OlGC8, was identified in the medaka fish Oryzias latipes by the isolation of full-length cDNA (4958 bp) and genomic DNA (14.3 kbp) clones. Phylogenetic analysis indicated that OlGC8 does not belong in any known vertebrate membrane GC subfamily. OlGC8 consists of an extracellular domain (214 residues), a transmembrane segment (19 residues), and an intracellular protein kinase-like domain (284 residues) and a cyclase catalytic domain (228 residues), although the extracellular domain is about half the length (around 450 residues) of other known vertebrate membrane GCs. OlGC8 transiently expressed in COS-7 cells exhibited only basal guanylyl cyclase activity. None of the known ligands (rat ANP, BNP, CNP, and C-ANF) and various medaka fish tissue extracts, which activated OlGC1, OlGC2, and OlGC7 differentially, stimulated basal activity, suggesting that OlGC8 is an orphan receptor. The OlGC8 gene consists of 24 exons and exists as a single copy on the medaka fish genome. Northern blot hybridization showed that a 5 kb-OlGC8 mRNA was expressed in the kidney and the testis at a high level and a 3.3 kb-OlGC8 mRNA was expressed only in the brain. The RNase protection, RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE), and reverse transcription-polymerase chain reaction (RT-PCR) analyses demonstrated that the 3.3 kb-OlGC8 mRNA detected in the brain is transcribed from the second transcription initiation site, and contains an intron at the position prior to the catalytic domain, the translation product of which appears to be a protein lacking the cyclase catalytic domain.
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PMID:Expression and genomic organization of a medaka fish novel membrane form of guanylyl cyclase/orphan receptor. 1277 30

(1) The sensitivity of the particulate guanylate cyclase-cyclic guanosine-3',5'-monophosphate (cGMP) system to atrial (ANP) and C-type (CNP) natriuretic peptides was investigated in aortae and mesenteric small arteries from wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (KO) mice. (2) ANP and CNP produced concentration-dependent relaxations of mouse aorta that were significantly attenuated by the natriuretic peptide receptor (NPR)-A/B antagonist HS-142-1 (10(-5) M). Both ANP and CNP were more potent in aortae from eNOS KO mice compared to WT. (3) The potency of ANP and CNP in aortae from WT animals was increased in the presence of the NOS inhibitor, N(G)-nitro-L-arginine (3 x 10(-4) M) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (5 x 10(-6) M). (4) In contrast, the potency of ANP and CNP in aortae from eNOS KO animals was reduced following pretreatment of tissues with supramaximal concentrations of the NO-donor, glyceryl trinitrate (3 x 10(-5) M, 30 min) or ANP (10(-7) M, 30 min). (5) Responses to acetylcholine in aortae from WT mice (dependent on the release of endothelium-derived NO) were significantly reduced following pretreatment of tissues with GTN (3 x 10(-5) M, 30 min) and ANP (10(-7) M, 30 min). (6) CNP and the NO-donor, spermine-NONOate caused concentration-dependent relaxations of mesenteric small arteries from WT animals that were significantly increased in eNOS KO mice compared to WT. ANP was unable to significantly relax mesenteric arteries from WT or eNOS KO animals. (7) In conclusion, both NPR-A- and NPR-B-linked pGC pathways are modulated by NO-cGMP in murine aorta and mesenteric small arteries and crossdesensitisation occurs between NPR subtypes. The biological activity of endothelium-derived NO is also influenced by the ambient concentration of NO and natriuretic peptides. Such an autoregulatory pathway may represent an important physiological homeostatic mechanism and link the paracrine activity of NO and CNP with the endocrine functions of ANP and BNP in the regulation of vascular tone and blood pressure.
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PMID:Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling. 1289 Jul 8

Atrial and brain (B-type) natriuretic peptides (ANP and BNP, respectively) are known to exert various cardioprotective effects. For instance, knocking out the expression of ANP, BNP, or their receptor, guanylyl cyclase-A, induces cardiac hypertrophy and/or fibrosis. The cardiac effects of elevated circulating natriuretic peptides are less well understood, however. We therefore compared angiotensin (Ang) II-induced cardiac hypertrophy and fibrosis in BNP-transgenic (Tg) mice, in which circulating BNP levels were elevated by increased secretion from the liver, and their non-Tg littermates. Left ventricular expression of Ang II type 1a receptor was similar in BNP-Tg and non-Tg mice, and there was no significant difference in the elevation of blood pressure elicited by chronic infusion or acute injection of Ang II. Nevertheless, cardiac hypertrophy and fibrosis were significantly diminished in BNP-Tg mice chronically infused with Ang II. In addition, ventricular activation of extracellular signal-regulated kinase (ERK) induced by acute injection of Ang II was also diminished in BNP-Tg mice, as was activation of ERK kinase (MEK). Conversely, expression of mitogen-activated protein kinase phosphatase (MKP) was significantly increased in the ventricles of BNP-Tg mice. Based on these findings, we conclude that elevated circulating BNP exerts cardioprotective effects via inhibition of a ventricular ERK pathway. The mechanism responsible for this inhibition likely involves 1) increased ventricular MKP expression and 2) inhibition of transduction mediators situated upstream of ERK.
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PMID:Angiotensin II-induced ventricular hypertrophy and extracellular signal-regulated kinase activation are suppressed in mice overexpressing brain natriuretic peptide in circulation. 1462 Nov 89

The natriuretic peptide family consists of three homologous members, atrial (ANP), B-type (BNP) and C-type natriuretic peptides (CNP). These small peptides activate specific membrane-bound guanylyl cyclase (GC) receptors (GC-A and GC-B), thus modulating cellular functions via the intracellular second messenger, cyclic GMP. Since the original discovery of cardiac ANP more than two decades ago, the application of gene targeting technology in mice has provided new valuable information regarding the molecular physiology and diverse biological functions of natriuretic peptides and their receptors. The GC-A and ANP gene knock-outs demonstrated that this signalling system is not only essential in the maintenance of normal blood pressure and volume, but also has local, growth-moderating functions within the heart itself. Disruption of the genes encoding BNP, CNP or the CNP-receptor, GC-B, demonstrated that these "natriuretic peptides" are in fact unlikely to physiologically regulate renal sodium excretion but instead may exert important autocrine/paracrine cGMP-mediated effects on cellular proliferation and differentiation in different tissues. Notably, the intestinal peptide uroguanylin, which activates a third guanylyl cyclase (GC-C), exerts diuretic/natriuretic activity and links the intestine and kidney in an endocrine way to modulate renal function in response to oral salt load. Reviewed here is the physiology and biochemistry of natriuretic peptides and their guanylyl cyclase receptors, with special focus on the information gained to date from targeted disruption of specific members of this peptide family, their receptors, or effector molecules in the murine system.
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PMID:Molecular physiology of natriuretic peptide signalling. 1496 65

In the human genome, sequence analysis indicates there are five functional transmembrane guanylyl cyclases, enzymes that synthesize the intracellular second messenger, cGMP. Two, GC-A and GC-B or NPR-A and NPR-B, are widely distributed receptors for atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide, more commonly known as ANP, BNP and CNP, respectively. One cyclase, GC-C or StaR, is predominantly found in the intestinal epithelium and is the receptor for guanylin and uroguanylin, as well as for the bacterial pathogen, heat-stable enterotoxin (Sta). The remaining two cyclases, GC-E and GC-F or RetGC-1 and RetGC-2, are expressed in the retina and regulate the dark cycle of phototransduction. Unlike the other family members, GC-E and GC-F have no known extracellular ligands. Instead, they are activated under low calcium conditions by guanylyl cyclase activating proteins called GCAPs. All five members consist of an extracellular ligand binding domain, single transmembrane spanning domain, and intracellular kinase homology, dimerization and guanylyl cyclase catalytic domains. In the first part of this review, the tissue expression, ligands and "knockout" phenotypes of each receptor are summarized and individual domains are compared. In the second part, regulation by ATP, calcium, protein kinase C and phosphorylation is discussed.
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PMID:Domain analysis of human transmembrane guanylyl cyclase receptors: implications for regulation. 1576 19

Atrial (ANP) and brain (BNP) natriuretic peptides are hormones of myocardial cell origin. These hormones bind to the natriuretic peptide A receptor (NPRA) throughout the body, stimulating cGMP production and playing a key role in blood pressure control. Because NPRA receptors are present on cardiomyocytes, we hypothesized that natriuretic peptides may have direct autocrine or paracrine effects on cardiomyocytes or adjacent cardiac cells. Because both natriuretic peptides and NPRA gene expression are upregulated in states of pressure overload, we speculated that the effects of the natriuretic peptides on cardiac structure and function would be most apparent after pressure overload. To attenuate cardiomyocyte NPRA activity, transgenic mice with cardiac specific expression of a dominant-negative (DN-NPRA) mutation (HCAT D 893A) in the NPRA receptor were created. Cardiac structure and function were assessed (avertin anesthesia) in the absence and presence of pressure overload produced by suprarenal aortic banding. In the absence of pressure overload, basal and BNP-stimulated guanylyl cyclase activity assessed in cardiac membrane fractions was reduced. However, systolic blood pressure, myocardial cGMP, log plasma ANP levels, and ventricular structure and function were similar in wild-type (WT-NPRA) and DN-NPRA mice. In the presence of pressure overload, myocardial cGMP levels were reduced, and ventricular hypertrophy, fibrosis, filling pressures, and mortality were increased in DN-NPRA compared with WT-NPRA mice. In addition to their hormonal effects, endogenous natriuretic peptides exert physiologically relevant autocrine and paracrine effects via cardiomyocyte NPRA receptors to modulate cardiac hypertrophy and fibrosis in response to pressure overload.
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PMID:Cardiac-specific attenuation of natriuretic peptide A receptor activity accentuates adverse cardiac remodeling and mortality in response to pressure overload. 1577 76

One of the principal loci involved in the regulatory action of atrial and brain natriuretic peptides (ANP and BNP) is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), whose ligand-binding efficiency and GC catalytic activity vary remarkably in different target cells and tissues. In its mature form, NPRA resides in the plasma membrane and contains an extracellular ligand-binding domain, a single transmembrane region, and the intracellular protein kinase-like homology domain (KHD) and guanylyl cyclase (GC) catalytic domain. NPRA is a dynamic cellular macromolecule that traverses through different compartments of the cell through its lifetime. Binding of ligand to NPRA triggers a complex array of signal transduction events and accelerates the endocytosis. The endocytic transport is important in regulating signal transduction, formation of specialized signaling complexes, and modulation of specific components of internalization events. The present review describes the experiments which reveal the internalization of ligand-receptor complexes of NPRA, receptor trafficking and recycling, and delivery of both ligand-receptor molecules into subcellular compartments. The ligand-receptor complexes of NPRA are finally degraded within the lysosomes. The experimental evidence provides a consensus forum, which establishes the endocytosis, cellular trafficking, sequestration, and metabolic processing of ANP/NPRA complexes in the intact cells. The discussion is afforded to address the experimental insights into the mechanisms that cells utilize in modulating the delivery and metabolic processing of ligand-bound NPRA into the cell interior.
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PMID:Internalization and trafficking of guanylyl cyclase/natriuretic peptide receptor-A. 1591 Oct 67


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