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 this study we compared the levels and responsiveness of atrial natriuretic peptide (ANP) receptors in neuronal and astrocyte glial cultures from spontaneously hypertensive (SH) and normotensive (Wistar-Kyoto: WKY) rat brain. Both neuronal and astrocyte glial cultures from the hypothalamus and brain stem of 1-day-old SH and WKY rats display specific high-affinity binding sites for 125I-labeled ANP. The presence of a large population of ANP-C receptors in each type of culture is indicated by the strong competition of 125I-ANP binding by the ring-deleted analogue of ANP [C-ANF-(4-23)]. In neuronal cultures from both strains, C-type natriuretic peptide (CNP-22) was the most effective natriuretic peptide in stimulating guanosine 3',5'-cyclic monophosphate (cGMP) levels, suggesting the presence of ANP-B receptors in these cells. By contrast, ANP was the most effective stimulator of cGMP levels in SH and WKY rat astrocyte glial cultures, suggesting the presence of ANP-A receptors. Here, we have determined that there is a decrease in the maximum binding capacity for 125I-ANP-specific binding in both SH rat neuronal and astrocyte glial cultures compared with their respective control cells. The stimulatory effects of CNP-22 on cGMP levels in SH rat neurons and of ANP on cGMP levels in SH rat astrocytes were significantly reduced compared with their respective WKY rat cultures. Our data suggest that the lower number of ANP receptors in SH rat neuronal and astrocyte glial cultures includes a reduction in the guanylate cyclase-coupled ANP receptors.
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PMID:ANP receptors in neurons and astrocytes from spontaneously hypertensive rat brain. 839 76

The cellular distribution of guanylyl cyclase coupled natriuretic peptide receptors type A (GC-A) and type B (GC-B) was examined by immunocytochemistry in normal rat kidney, and compared with the distribution of the vacuolar H(+)-ATPase. Staining for GC-A was found in glomeruli, thin limbs of Henle's loop, cortical collecting tubule, and inner medullary collecting duct. Staining for GC-B was found in glomeruli and the same nephron sections as GC-A, with the exception of the thin limbs. In the cortical collecting tubule, GC-A was found in both principal and intercalated cells; GC-B was restricted to the apical pole of alpha intercalated cells. In inner medullary collecting duct cells, GC-A was located on the basal membrane, whereas GC-B was found in the apical pole. The different pattern of polarization of natriuretic peptide receptors in the inner medulla provides a plausible basis for the different physiologic effects of atrial natriuretic factor and C-type natriuretic peptide. The results also suggest the possibility that GC-B is involved in the regulation of bicarbonate transport in the cortical collecting tubule.
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PMID:Natriuretic peptide receptors A and B have different cellular distributions in rat kidney. 858 68

The polarized expression of guanylyl cyclase-coupled natriuretic peptide receptors, types A (GC-A) and B (GC-B), was measured in inner medullary collecting ducts (IMCD) of normal and ischemic rat kidneys, as well as in IMCD cells. Exposure of normal rat kidney medulla to an anti-GC-A antibody demonstrated a propensity of receptor staining on the cellular basal membrane. The polarization of GC-A receptors was lost in the ischemic kidney. The maximal binding capacity of 125I-atrial natriuretic factor (ANF) to the basal membrane of the inner medullary cell line mIMCD-K2 was five times greater than that to the apical membrane. ANF or C-type natriuretic peptide (CNP) added to the basal side of cultured cells resulted in guanosine 3',5'-cyclic monophosphate formation that was greater than when applied to the apical side. Depletion of ATP stores in cultured cells was followed by an increase of 125I-ANF binding to apical cellular membranes. Similar results were obtained when receptor guanylyl cyclase activity was assayed. In conclusion, these results suggest that functional GC-A and GC-B receptors are present predominantly on the basal membrane of IMCD. However, depletion of cellular ATP stores such as in ischemia is followed by a partial loss of polarization.
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PMID:Polarized distribution of renal natriuretic peptide receptors in normal physiology and ischemia. 859 88

Adipose tissue of the mesenteric territory contains large quantities of natriuretic peptide receptors (NPR) mainly of the NPR-C subtype. Guanylyl cyclase-bound receptors are also present since atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are equally potent in activating this enzyme. While searching for a potential biological role for NP in adipocytes we observed that ANP-mediated generation of cyclic GMP (cGMP) was potentiated when the cells were simultaneously treated with isoproterenol. Indeed, isoproterenol, a beta-adrenergic agonist, and forskolin, an activator of adenylyl cyclase, can both double or triple cGMP production in response to ANF stimulation. There was a direct correlation between the level of cyclic AMP (cAMP) generated and the level of NP-mediated cGMP production suggesting that a cAMP-dependent mechanism may be responsible of this potentiation. To determine whether or not this phenomenon was unique to adipocytes, NPR subtypes were characterized in 4 established cell lines and their cAMP-dependent cGMP behavior examined. A10 and A7r5 smooth muscle cells showed identical ratio of NPR subtypes with about 95% NPR-C and 5% NPR-B. PC12 cells presented 100% NPR-A and NIH 3T3 fibroblasts 50% NPR-C and 50% NPR-B. Regardless of the NPR subtype, forskolin could not potentiate the cGMP generation in these cell lines. These data indicate that the cAMP-dependent potentiation of the NP-mediated cGMP production is unique to adipocytes, appears independent of the guanylyl cyclase-linked NPR subtypes and may be involved in the sensitization of the guanylyl cyclase domain of NPR for a potential biological role of NP in the adipose tissue.
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PMID:Specific potentiation by cyclic AMP of natriuretic peptide-mediated cyclic GMP production in adipose tissue. 864 24

Blood pressure in the amphibian pulmonary circulation is relatively high because a single ventricle serves both the systemic and pulmonary circulation, creating a high degree of plasma filtration from pulmonary capillaries. Previous studies have shown that lung atrial natriuretic factor (ANF) may have an important physiological function in preventing edema in mammals. In this study, we report the presence of the complete ANF system in the lungs of the toad Bufo paracnemis. Radioimmunoassay of tissue homogenates revealed that toad lung ANF concentration was approximately twice as high (928.5 +/- 83.0 pg mg-1 protein) as that of lung tissue in mammals of a similar size. The amount of ANF was significantly higher in the left than in the right atrium (15.0 +/- 1.2 versus 1.9 +/- 0.8 ng mg-1 protein; N = 4, P < 0.001), while the ventricle contained 488.3 +/- 41.8 pg mg-1 protein. In extracts of both lungs and atria, high-performance liquid chromatography revealed two forms of the peptide; prohormone and a carboxy-terminal peptide of low molecular mass, which is the biologically active form of peptide. The presence of the prohormone suggests that ANF is synthesized in toad lungs and atria. Characterization of toad lung receptors by a competitive binding assay demonstrated three different subtypes of ANF receptors: the guanylyl cyclase (GC) receptors, GC-A and GC-B, as well as clearance (C) receptors. We conclude that the toad Bufo paracnemis has a well-developed complete ANF system in the lung, suggesting that it has a role in toad lung physiology.
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PMID:Characterization of the atrial natriuretic factor system in lungs of the toad Bufo paracnemis. 869 54

Physiological actions of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are elaborated by membrane-bound natriuretic peptide receptors (NPRs). These receptors possess intracellular guanylate cyclase domains that mobilize cyclic guanosine monophosphate upon binding of peptide. Two distinct NPR subtypes have been described in brain: the NPR-A selectively binds ANP, whereas NPR-B exhibits high affinity for CNP. To define further the potential domains of ANP and CNP action in brain, the present study used in situ hybridization histochemistry to map NPR-A and NPR-B mRNA-expressing cell populations. Significant levels of neuronal NPR-A mRNA expression were observed only in the mitral cell layer of the olfactory bulb, medial habenula, subfornical organ, and area postrema. Expression of NPR-A mRNA was observed in forebrain white matter tracts, suggesting synthesis in glial cells. In contrast, NPR-B mRNA was widely expressed throughout the neuraxis. In the telencephalon, signal was abundant throughout limbic cortex and neocortex, olfactory bulb, hippocampus, and amygdala. Intense NPR-B mRNA hybridization was observed in preoptic-hypothalamic neuroendocrine circuits and in motor nuclei of cranial nerves. Intermediate expression of NPR-B mRNA was observed in brainstem nuclei controlling autonomic function. Labeling for NPR-B but not NPR-A mRNA was observed in pituicytes in the neural lobe of the pituitary and in scattered cells of the anterior pituitary. These results suggest that CNP is the primary biologically active natriuretic peptide in brain. In contrast with NPR-B, NPR-A appears to be expressed largely in restricted cell populations containing high levels of ANP and in circumventricular organs. These data implicate the NPR-A in autoregulation of ANP neurons and central registration of cardiac ANP release.
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PMID:Localization of natriuretic peptide-activated guanylate cyclase mRNAs in the rat brain. 872 93

The inhibitory effect of atrial natriuretic peptide (ANP) on angiotensin II (AII)-stimulated aldosterone secretion has been previously studied in rat and bovine adrenal zona glomerulosa cells in primary culture. However the understanding of the mode of action of ANP at the molecular level has been hampered by limitations of those primary cell culture systems and by the lack of cell lines from human adrenal cortex. Here we demonstrate the presence of fully functional ANP receptors in the recently characterized AII-responsive adrenocortical carcinoma cell line H295R. Specific saturable binding of 125I-rANP to H295R cell membrane preparations revealed a single class of high affinity binding sites with a density of 20 fmol/mg of protein. The pharmacological profile of this ANP receptor was documented by competitive binding of 125I-rANP with naturally occurring natriuretic peptides. rANP was the most potent with a Kd of 42 pM. pBNP32 was less potent with a Kd of 174 pM. 125I-rANP binding was not competed by pCNP (NPRB-specific ligand) nor by C-ANF (NPRC-specific ligand). Photoaffinity labeling of membrane preparations with 125I-BPA-ANP revealed a single specific protein of molecular weight around 130 kDa. This protein was further identified by immunodetection with a specific antibody directed to the human ANP-specific receptor NPRA. Natriuretic peptides stimulated cGMP production by the receptor-coupled guanylate cyclase with the same specificity. Aldosterone production by AII-stimulated H295R cells was dose-dependently inhibited by rANP with an ED50 of 1.5 nM. In addition, we used this model to test two chimeric analogs of ANP and BNP. pBNP1 and pBNP3 were, respectively, 4- and 2-fold more potent than rANP in competing for 125I-rANP binding with Kd of 10 and 20 pM. pBNP1 was 24-fold more potent in inhibiting AII-stimulated aldosterone production with ED50 of 63 pM. pBNP1 is therefore the most potent natriuretic peptide analog tested. In summary, the human H295R cell line contains NPRA receptors positively coupled to the particulate guanylate cyclase and that antagonize angiotensin II stimulation of aldosterone secretion.
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PMID:The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. 873 99

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

Functional studies indicate that natriuretic peptides have direct effects on Leydig cells of the testis. In this report, we demonstrate local synthesis of one member of the natriuretic peptide family, C-type natriuretic peptide (CNP), in Leydig cells of human testes. Using RT-PCR assays, messenger RNA (mRNA) for the CNP precursor was detected in human testis and found to be prominently expressed in Leydig cells. Immunohistochemical analyses revealed CNP to be almost exclusively associated with Leydig cells. Distinct differences in the staining intensity-including cells without detectable staining-suggest a heterogeneity of CNP expression within the Leydig cells. Moreover, the presence of transcripts for the CNP receptor, a particulate guanylate cyclase, termed GC-B, was demonstrated by RT-PCR in human testis and in isolated Leydig cells. The expression of this receptor in human testis membranes could be confirmed by affinity labeling with 125I-labeled CNP. These findings demonstrate, for the first time, the production of a natriuretic peptide in human Leydig cells. The occurrence of CNP and its receptor in the human testis points to a local role of the peptide, presumably acting in an auto- or paracrine manner to modulate organ-specific functions.
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PMID:Natriuretic peptides in the human testis: evidence for a potential role of C-type natriuretic peptide in Leydig cells. 895 35

We have previously shown that rat ovaries synthesize atrial natriuretic peptide (ANP) and express the cognate guanylyl cyclase (GC-A and GC-B) receptors for ANP. Since another natriuretic peptide, termed the C-type natriuretic peptide (CNP), can also interact with these receptors, we have investigated whether rat ovaries express CNP and if so, whether the concentration of this natriuretic peptide and the guanylyl-cyclase receptors are influenced by the estrous cycle. CNP mRNA was detected in rat ovaries using a reverse transcription (RT) polymerase chain reaction (PCR) strategy. RIA of ovarian extracts, obtained at the individual days of the estrous cycle, revealed the presence of immunoreactive CNP. The highest levels of CNP were detected at proestrus and were approximately 4-fold higher than the levels seen at any other stage of the cycle. GC-A and GC-B receptors were detected using quantitative autoradiography after application of either [125I]ANP or [125I]-tyr0CNP to sections of frozen ovaries. The highest specific binding of each radiolabeled ligand was seen in ovaries from proestrous animals. The GC-B receptors were localized to the membrana granulosa of developing ovarian follicles. Using quantitative PCR, we determined that levels of GC-A and GC-B mRNAs were highest in the ovaries of proestrous animals and were approximately 2- to 3-fold higher than the levels seen at diestrus. These findings demonstrate that a natriuretic peptide system, consisting of ligands and receptors, is present in the rat ovary. Since CNP and the GC receptors show coordinate estrous cycle-dependent variation with maximal expression at proestrus, we speculate that the natriuretic peptides may play an important role in either the development of ovulatory follicles or in the ovulatory process.
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PMID:C-type natriuretic peptide and the guanylyl cyclase receptors in the rat ovary are modulated by the estrous cycle. 900 33


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