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)

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs.
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PMID:The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. 1037 27

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

Histochemical reaction of NADPH-diaphorase (NOS-NADPH-d) was used to identify NO synthesis. A 30-min 0.1 microg microg/kg/min ANP infusion led to about a 10% and 35% increase in small and large intestine enterocytes stain respectively. This increase was abolished by a bolus of 1 mg/kg L-NAME before ANP infusion in small intestine, and partially abolished it in colon. Incubation of small and large intestine with 0.5 microM ANP increased stain at about 20%. In both tissues the preincubation with 0.1 mM L-NAME abolished the ANP effect. Incubation with 0.1 mM 8-Br-cGMP enhanced staining about 70% and 30% in small and large intestine respectively. Our results show that ANP enhances NOS-NADPH-d activity, suggesting that ANP stimulates NO synthase in enterocytes by L-arginine-NO pathway. 8-Br-cGMP mimicked the effect of ANP described above. Therefore, the guanylate cyclase-coupled natriuretic receptors, NPR-A and NPR-B, probably mediate this ANP effect.
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PMID:Atrial natriuretic peptide effect on NADPH-diaphorase in rat intestinal tract. 1046 14

C-type natriuretic peptide (CNP), the third member of the atrial natriuretic peptide family, acts via guanylyl cyclase containing GC-B receptors to stimulate cyclic guanosine 3',5' monophosphate (cGMP) accumulation in the gonadotrope-derived alphaT3-1 cell line and rat pituitary cells. This effect is inhibited by concomitant activation of the phospholipase C (PLC)-coupled gonadotrophin hormone-releasing hormone (GnRH) receptors in these cells. Since GnRH stimulates gonadotrophin secretion from gonadotropes by increasing the cytosolic Ca2+ concentration ([Ca2+]i) and natriuretic peptides have been found to influence PLC/Ca2+ signalling in other systems, we have investigated whether CNP can alter basal or GnRH-stimulated changes in [Ca2+]i in alphaT3-1 cells. In Ca 2+-containing medium, 10(-7) M CNP modestly, but significantly increased [Ca2+]i over several min, but subsequently inhibited the elevation of [Ca2+]i in response to 10(-7) M GnRH in both Ca2+-containing and Ca2+-free medium. This inhibitory effect was mimicked by 10(-6) M 8-Br-cGMP, but not by ANP, indicating mediation by cyclic GMP and the CNP-specific GC-B receptor. However, basal and GnRH-stimulated inositol (1,4,5) trisphosphate (Ins(1,4,5)P3) generation were not measurably affected by CNP, and CNP failed to affect thapsigargin-induced capacitative Ca2+ entry. Thus, it appears that the cross-talk between CNP and GnRH in these cells is reciprocal in that GnRH modulates CNP effects on cGMP generation, whereas, CNP modulates GnRH effects on Ca2+ mobilisation.
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PMID:C-type natriuretic peptide (CNP) effects on intracellular calcium [Ca2+]i in mouse gonadotrope-derived alphaT3-1 cell line. 1053 7

Monoamine oxidase (MAO) catalyzes the biological degradation of the neurotransmitters monoamines. The altered substrate specificity of MAO may be of pathogenic importance in some cases and MAO inhibitors showed a therapeutical effect in the experimental setting. Analyzing the efficacy of various compounds in inhibiting MAO A and B revealed new approaches to designing new-generation MAO inhibitors. Tribulin is a fraction of endogenous MAO inhibitors that are present in human and animal tissues and biological fluids. Isatin is an endogenous indole which was initially derived from a tribulin fraction. An investigation of the biological properties of tribulin revealed its heterogeneity and some chemical components were identified. It was shown that deficiency of tribulin components that selectively inhibited MAO A long with a larger number of molecules of this enzyme might be of great importance for the development of alcoholism. In addition to MAO inhibition, the physiological concentrations of isatin inhibited the receptor-binding of atrial natriuretic peptides and ANP-stimulated guanylate cyclase (GC). The sensitivity of ANP-GC to isatin might be allosterically regulated. Selective antagonists of natriuretic peptide receptors were found among isatin analogues which may be an effective pharmacological tool for further studies of the role of natriuretic peptides in the body.
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PMID:[Monoamine oxidase, tribulin, isatin: basic and applied medical aspects]. 1057 64

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

Natriuretic peptides form a family of structurally related peptides known to regulate salt and water homeostasis and to cause vasodilation. Synthesis of atrial (ANP), brain (BNP), and C-type (CNP) natriuretic peptides occurs mainly in the heart and brain and has been identified recently in the female reproductive tract. The expression of ANP and CNP as well as their cognate guanylyl cyclase receptors (NPR-A and NPR-B, respectively) have been detected in the rat ovary. We have shown previously that the expression of the natriuretic peptides and their receptors in the rat ovary appears to be modulated by the estrous cycle. In the present study we have evaluated the expression of the natriuretic peptide system (peptide and receptor) in ovarian cells (granulosa and thecal-interstitial cells) obtained from immature female rats treated with either diethylstilbestrol (DES), an estrogen analog, or equine CG (eCG), a gonadotropin that possesses both LH and FSH activity. Using a whole cell RRA, we found that CNP binding was increased by 2-fold in granulosa cells taken from animals treated with either DES or eCG. Semiquantitative RT-PCR revealed that granulosa cells from DES- or eCG-treated animals have increased levels of NPR-B messenger RNA (mRNA) transcripts, which was in good agreement with the increased binding. The activity of the receptors was assessed by ligand-dependent stimulation of cGMP release. CNP, but not ANP, stimulated the release of cGMP from granulosa cells obtained from DES-treated, but not from eCG-treated, animals. The relative levels of CNP mRNA in granulosa cells were unaltered by either DES or eCG treatment. In contrast, CNP mRNA levels were increased more than 2-fold, but only in theca-interstitial from the eCG-treated animals. Our results indicate that CNP and NPR-B are expressed in the ovary, and their expression is responsive to hormonal treatments. Furthermore, expression of these components of the natriuretic peptide system appears to be compartmentalized, with CNP being derived from the extrafollicular compartment and acting, through NPR-B, on the granulosa cells.
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PMID:B-type natriuretic peptide receptor expression and activity are hormonally regulated in rat ovarian cells. 1065 Sep 35

The messenger molecule cyclic guanosine monophosphate (cGMP) is produced by different isoforms of the enzyme guanylate cyclase (GC). Natriuretic peptides (ANP and CNP) bind to and activate particulate GCs, whereas NO and CO activate a soluble form of GC. The specific relevance of the cGMP system for reproductive functions has been recently demonstrated by the successful use of sildenafil (Viagra), an inhibitor of cGMP-specific phosphodiesterase type 5, for the treatment of erectile dysfunction. In the testis, cGMP signal transduction pathways are involved in a variety of local functions, based on autocrine or paracrine effects. In particular, cGMP has been suggested to influence motility in spermatozoa, development of testicular germ cells, relaxation of peritubular lamina propria cells, testosterone synthesis in Leydig cells and dilatation of testicular blood vessels. The physiological significance of cGMP accumulation in Scrtoli cells is not yet clear. Taken as a whole, the evidence suggests that cGMP-mediated processes might influence both the potentia coeundi within the penis and the potentia generandi at various levels within the testis.
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PMID:Multiple roles of the messenger molecule cGMP in testicular function. 1070 69

The presence of receptor subtypes for natriuretic peptides (NPs) and endothelin (ET) in the epididymis of the freshwater turtle, Amyda japonica, was examined by quantitative in vitro autoradiography using iodinated mammalian-type atrial NP ((125)I-ANP((1-28))), phylogenically conserved C-type NP ((125)I-[Tyr(0)]-CNP((1-22))), and ET-1 ((125)I-ET-1) as radiolabeled ligands. To characterize NP receptor (NPR) subtypes, we also performed an activation of particulate guanylyl cyclase (GC) in membranes of the epididymis by NPs. Specific (125)I-ANP((1-28)) and (125)I-[Tyr(0)]-CNP((1-22)) bindings were localized in surrounding smooth muscle cell layer of the duct of the epididymis with an apparent dissociation constant (K(d)) of 0.84+/-0.15 and 1.74+/-0.39 nM and a maximal binding capacity (B(max)) of 0.47+/-0.11 and 0.08+/-0.01 fmol/mm(2), respectively. Bindings of (125)I-ANP((1-28)) and (125)I-[Tyr(0)]-CNP((1-22)) to these sites were also displaced by des[Gln(18),Ser(19),Gly(20), Leu(21),Gly(22)]ANF((4-23)), a specific ligand of the NP clearance receptor. Production of 3',5'-cyclic guanosine monophosphate by particulate GC in membranes of the epididymis was stimulated by ANP((1-28)), BNP((1-26)), and CNP((1-22)). Receptor subtypes for ET in the epididymis were characterized by competition with BQ 123 and BQ 788 as specific antagonists for ET receptors, type A (ET(A)) and type B (ET(B)) subtypes, respectively. Specific (125)I-ET-1 bindings were localized in the smooth muscle cell layer of the duct of the epididymis with K(d) and B(max) of 0.21+/-0.03 nM and 0.52+/-0.05 fmol/mm(2), respectively. These specific bindings were potently inhibited in a dose-dependent manner by BQ 123, whereas BQ 788 (10 microM) was not in competing for specific (125)I-ET-1 bindings in this structure. Therefore, these results indicate that specific NP and ET receptors are localized in surrounding smooth muscle cells of the duct of the epididymis of the freshwater turtle. It is also suggested that biological and clearance NPR-like subtypes coexist in these cells, and the predominant ET receptor subtype in this tissue is the ET(A)-like receptor. The localization of specific receptors for NPs and ET in the epididymis may be involved in the control of the transport of sperm in the freshwater turtle.
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PMID:Localization of receptors for natriuretic peptide and endothelin in the duct of the epididymis of the freshwater turtle. 1075 64

Experiments were designed to determine mechanisms by which Dendroaspis natriuretic peptide (DNP) causes relaxations in coronary arteries. Rings of canine left circumflex artery with and without endothelium were suspended in organ chambers filled with Krebs-Ringer bicarbonate solution (37 degrees C, bubbled with 95% O2/5% CO2). Concentration-response curves to DNP (10(-10) to 3 x 10(-7) M) were obtained in arteries contracted with prostaglandin (PGF(2alpha), 2 x 10(-6) M), either in the absence or the presence of C-ANP (10(-6) M) to inhibit natriuretic clearance receptors; indomethacin to inhibit cyclooxygenase (INDO, 10(-5) M), N(G)-monomethyl-L-arginine to inhibit production of nitric oxide (L-NMMA; 10(-4) M), HS-142-1 to inhibit particulate guanylate cyclase (10(-5) M); 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one to inhibit soluble guanylate cyclase (ODQ; 10(-5) M), or tetraethylammonium to inhibit potassium channels (TEA; 10(-3) or 10(-2) M). Relaxations to DNP were greater in rings with than in those without endothelium. C-ANP significantly attenuated relaxations to DNP only in rings with endothelium. HS-146-1 but not INDO, L-NMMA, ODQ, and TEA significantly reduced relaxations to DNP in rings with and without endothelium contracted with PGF(2alpha). These results suggest that the endothelium augments inhibitory effects of DNP and that natriuretic clearance receptors mediate this component of the response to DNP in canine coronary arteries. In addition, relaxations to DNP in canine arterial smooth muscle involve activation of particulate guanylate cyclase but not hyperpolarization.
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PMID:Mechanism of relaxations to dendroaspis natriuretic peptide in canine coronary arteries. 1077 93


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