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)

An ANF-like material was detected by radioimmunoassay in the isolated perfused rabbit kidney. The production of ANF-like material after 90 min of perfusion under hypoxia was 3000 pg/ml vs 500 pg/ml under normoxia or control conditions. This material is partially inactivated by heat treatment at 100 degrees C for 5 min and is absorbed on a SEP-PAK column (C18, Waters) but, unlike ANF, cannot be recovered from the column. On Sephadex G25 chromatography, elution in water yielded two active fractions, one corresponding to the solvent front and the second obtained after one column volume. Four fractions with biological activity were eluted with water from Sephacryl 200. Several fractions were tested on rabbit aorta preconstricted with 1 microM phenylephrine, without removal of endothelial cells. Treatment of T84 cells in culture by the crude material promoted a dose-related increase (1:2, 1:5, 1:10) of the generation of cyclic GMP. In contrast to our material, ANF (atriopeptin III, 1 microM-10 fM) failed to activate guanylate cyclase in T84 cells, while the heat-stable E. coli enterotoxin (STa) significantly increased cyclic GMP levels at the dose of 5 microM. We propose that a new ANF/urodilatin/ST-like material was generated by the hypoxic kidney under perfusion, which we name FNS (Factor Natriureticus Similis).
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PMID:Partial characterization of an ANF/urodilatin-like substance released from perfused rabbit kidney under hypoxia. 822 Feb 71

Uroguanylin and guanylin are peptides isolated from urine and intestinal mucosa, which regulate cyclic GMP production in enterocytes by activating an apical membrane, receptor-guanylate cyclase. This study extended our previous findings, which showed that colonic mucosa of opossums contained uroguanylin and guanylin peptides, by purifying prouroguanylin and proguanylin from this tissue. Prouroguanylin and proguanylin coeluted from Sephadex G-75 gelfiltration columns with a similar molecular size between 6 and 12 kDa. Mass spectrometry indicated that proguanylin (approximately 8.7 kDa) had a 10% lower molecular mass than prouroguanylin (approximately 9.7 kDa). Isoelectric focusing separated prouroguanylin (pI approximately 4.5) from proguanylin (pI approximately 7.5). N-terminal sequence analysis of reverse phrase-HPLC purified prohormones revealed 13 amino acids in opossum proguanylin that shared 77-85% identity with human and rat proguanylin, but only 23% identity with opossum prouroguanylin. The N-terminal 19 residues obtained for opossum prouroguanylin shared 32-42% identity with rat and human proguanylin. Prouroguanylin and proguanylin were both inactive and required pretreatment with proteases to elicit cyclic GMP responses in T84 cells. V8 protease treatment of proguanylin liberated a bioactive, 16-amino acid form of guanylin. Chymotrypsin treatment activated prouroguanylin, but inactivated the bioactive peptide domain within proguanylin. In summary, colonic mucosa contains the bioactive peptide and inactive prohormone forms of uroguanylin and guanylin. Thus, after proteolytic processing of prouroguanylin and proguanylin, bioactive uroguanylin and guanylin could both function to regulate guanylate cyclase activity by autocrine and/or paracrine actions on enterocytes. Also, these peptide hormones are implicated in an intestinal-renal axis for the endocrine regulation of salt and water homeostasis.
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PMID:Prouroguanylin and proguanylin: purification from colon, structure, and modulation of bioactivity by proteases. 853 21

Hamsters with cardiomyopathy (CMO), an experimental model of congestive heart failure, display stimulated renin-angiotensin-aldosterone and enhanced sympathetic nervous activity, all factors that lead to sodium retention, volume expansion and subsequent elevation of plasma atrial natriuretic factor (ANF) by the cardiac atria. However, sodium and water retention persist in CMO, indicating hyporesponsiveness to endogenous ANF. These studies were undertaken to fully characterize renal ANF receptor subtypes in normal hamsters and to evaluate whether alterations in renal ANF receptors may contribute to renal resistance to ANF in cardiomyopathy. Transcripts of the guanylyl cyclase-A (GC-A) and guanylyl cyclase B (GC-B) receptors were detected by quantitative polymerase chain reaction (PCR) in renal cortex, and outer and inner medullas. Compared to normal controls, the cardiomyopathic hamster's GC-A mRNA was similar in cortex but significantly increased in outer and inner medulla. Levels of GC-B mRNA were not altered by the disease. On the other hand, competitive binding studies, autoradiography, and affinity cross-linking demonstrated the absence of functional GC-B receptors in the kidney glomeruli and inner medulla. Also, C-type natriuretic peptide (CNP), the natural ligand for the GC-B receptors, failed to stimulate glomerular production of its second messenger cGMP. In CMO, sodium and water excretion were significantly reduced despite elevated plasma ANF (50.5 +/- 11.1 vs. 309.4 +/- 32.6 pg/ml, P < 0.001). Competitive binding studies of renal glomerular ANF receptors revealed no change in total receptor density, Bmax (369.6 +/- 27.4 vs. 282.8 +/- 26.2 fmol/mg protein), nor in dissociation constant, Kd (647.4 +/- 79.4 vs. 648.5 +/- 22.9 pM). Also, ANF-C receptor density (254.3 +/- 24.8 vs. 233.8 +/- 23.5 fmol/mg protein), nor affinity were affected by heart failure. Inner medullary receptors were exclusively of the GC-A subtype with Bmax (153.2 +/- 26.4 vs. 134.5 +/- 21.2 fmol/mg protein) and Kd (395.7 +/- 148.0 vs. 285.8 +/- 45.0 pM) not altered by cardiomyopathy. The increase in ANF-stimulated glomerular cGMP production was similar in normal and CMO hamsters (94- vs. 75-fold). These results demonstrate that renal ANF receptors do not contribute to the attenuated renal responses to ANF in hamster cardiomyopathy.
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PMID:Renal atrial natriuretic factor receptors in hamster cardiomyopathy. 858 47

Uroguanylin, a 16-amino acid peptide, is an endogenous activator of intestinal and possibly renal guanylate cyclase C (GC-C). Using two synthetic topological isoforms of human uroguanylin, one bioactive, the other inactive, we prepared two antisera specific for the individual isoforms and developed sensitive radioimmunoassay (RIAs). The respective plasma concentrations of the bioactive and inactive uroguanylins in the normal individuals tested were 5.0 +/- 0.3 fmol/ml (mean +/- SE) and 1.6 +/- 0.1 fmol/ml. These concentrations increased in chronic renal failure (CRF). The major endogenous uroguanylin molecule in normal human urine was 16 amino acids long, whereas in the plasma and urine of CRF patients the major molecule was 10-kDa prouroguanylin. The RlAs established are promising tools for clarifying the physiological functions and pathophysiological implications of uroguanylin in water and electrolyte homeostasis.
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PMID:Identification of biologically active and inactive human uroguanylins in plasma and urine and their increases in renal insufficiency. 860 8

Nitric oxide has a diuretic effect in vivo. We have shown that nitric oxide inhibits antidiuretic hormone-stimulated osmotic water permeability in the collecting duct; however, the mechanism by which this occurs is unknown. We hypothesized that inhibition of antidiuretic hormone-stimulated water permeability by nitric oxide in the collecting duct is the result of activation of cGMP-dependent protein kinase, which in turn decreases intracellular cAMP. To test this hypothesis, we microperfused cortical collecting ducts. Antidiuretic hormone-stimulated water permeability was 317 +/- 47 microm/s (P < .001). Addition of spermine NONOate, a nitric oxide donor, to the bath decreased water permeability to 74 +/- 38 microm/s (P < .002). In the presence of LY 83583, an inhibitor of soluble guanylate cyclase, spermine NONOate did not change water permeability. Addition of spermine NONOate increased cGMP production (P < .01). In the presence of the cGMP-dependent protein kinase inhibitor, spermine NONOate did not change water permeability. Since antidiuretic hormone increases water permeability by increasing cAMP, we hypothesized that nitric oxide inhibits water permeability by decreasing cAMP. In tubules pretreated with antidiuretic hormone, intracellular cAMP was 18.9 +/- 3.9 fmol/mm. In tubules treated with antidiuretic hormone and spermine NONOate, cAMP was 9.3 +/- 1.7 fmol/mm (P < .03). We also examined the effect of spermine NONOate on dibutyryl-cAMP-stimulated water permeability. In the presence of dibutyryl-cAMP, water permeability was 388 +/- 30 microm/s. Addition of spermine NONOate had no significant effect on water permeability. Time controls and inhibitors by themselves did not change antidiuretic hormone-stimulated water permeability. We concluded that nitric oxide decreases antidiuretic hormone-stimulated water permeability by increasing cGMP via soluble guanylate cyclase, activating cGMP-dependent protein kinase and decreasing cAMP.
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PMID:Mechanism of the nitric oxide-induced blockade of collecting duct water permeability. 861 24

Guanylin (GCAP-I, guanylate cyclase activating peptide I) and uroguanylin (GCAP-II, guanylate cyclase activating peptide II) are regulatory peptides involved in the regulation of the intestinal chloride / water balance. They share significant structural homology to the E. coli enterotoxin STa, which binds to the particulate guanylyl cyclase C causing diarrhea in mammals. In this study we report the functional analysis of the guanylin / GCAP-I gene promoter region. By means of the luciferase reporter gene assay, we demonstrate a strong promoter activity in T84 cells. Especially the first 160 bp of the 5'-flanking region of the gene seem to be essential for gene induction. Our findings are the basis for further identification of important regulatory elements of the corresponding gene.
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PMID:Functional analysis of the human guanylin gene promoter. 871 1

Guanylin is a recently discovered peptide hormone that activates intestinal guanylate cyclase (GC-C) and thereby stimulates intestinal chloride secretion. Immunohistochemistry showed its presence in enterochromaffin (EC) cells of the gut. In vitro studies suggested that guanylin plays an important role in the endogenous modulation of intestinal salt and water secretion. In the present study the concentration of circulating immunoreactive (IR)-guanylin in plasma of patients with intestinal diarrhoea due to chronic bowel inflammation and patients with carcinoid tumours were measured with a specific radioimmunoassay. In 22 patients with Crohn's disease and eight patients with ulcerative colitis, plasma concentrations of IR-guanylin were 44 +/- 3 and 42 +/- 4 fmol mL-1, respectively. Levels were not different from that in 44 healthy volunteers suggesting that the circulating hormone is not involved in diarrhoea of these patients. In 17 patients with symptomatic carcinoid tumors the median concentration of circulating IR-guanylin was significantly enhanced (94 +/- 16 fmol mL-1, range 37-312 fmol mL-1). Immunohistochemistry revealed the presence of immunoreactive guanylin in carcinoid tissues, suggesting that these tumours co-release guanylin along with their usual resident hormone, serotonin. Enhanced local secretion of guanylin may play a causal role in diarrhoea of these patients and its elevation in plasma may be of diagnostic value in this type of endocrine tumours.
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PMID:Circulating and tissue guanylin immunoreactivity in intestinal secretory diarrhoea. 871 28

Guanylin and uroguanylin are small, heat-stable peptides that were initially isolated from rat jejunum and opossum urine, respectively. Both peptides bind to and activate a common set of apical membrane receptors that contain a guanylate cyclase catalytic domain within the receptor molecule. The guanylin/uroguanylin receptors are found on the luminal surface of epithelial cells lining the intestinal tract and renal proximal tubules as well as in other organs. Activation of receptor-guanylate cyclase signaling molecules by uroguanylin or guanylin elicits large increases in guanosine cyclic 3'-5' monophosphate (cGMP) production. Intracellular accumulation of this second messenger in target cells leads to the stimulation of intestinal chloride secretion, culminating in the enhancement of salt and water secretion into the intestinal lumen as well as increases in urinary sodium, potassium, and water excretion by actions of cGMP in the renal tubules. Uroguanylin and guanylin are produced throughout the intestinal mucosa and, surprisingly, uroguanylin messenger RNA (mRNA) is also expressed in both atria and ventricles of the heart. Both proguanylin and prouroguanylin are inactive polypeptides, and activation is accomplished by cleavage and release of the COOH-terminal peptides, guanylin and uroguanylin. Uroguanylin is postulated to function as an intestinal natriuretic hormone because: (1) prouroguanylin and uroguanylin both circulate in the plasma of normal animals; (2) uroguanylin is the predominant peptide agonist appearing in the filtrate and, thus, in urine; (3) the receptors for uroguanylin are localized to the apical membranes of renal tubular cells; (4) uroguanylin is substantially more potent than guanylin in eliciting a natriuresis; and (5) uroguanylin is expressed in the duodenum and myocardium, which are appropriate sites in the body for the production and release of a hormone that acts as a natriuretic agonist in vivo. The hypothesis that uroguanylin links the intestine with the kidney in an endocrine axis also predicts that the secretion of uroguanylin from the intestinal mucosa will be influenced by dietary levels of salt. Accordingly, plasma levels of uroguanylin or prouroguanylin should be influenced by oral salt loads. Future investigations will focus on the basic endocrinology of uroguanylin to provide answers to this intriguing question. In conclusion, uroguanylin is a candidate for a physiological role as an intestinal natriuretic hormone. Key features of the biology of uroguanylin provide a putative explanation for the substantial natriuresis that occurs in human subjects and experimental animals after an oral salt load. Moreover, uroguanylin and guanylin participate cooperatively in an intrinsic pathway for regulation of intestinal salt and water transport, thus providing another means of influencing salt and water homeostasis in addition to the renal actions of uroguanylin.
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PMID:Salt and water homeostasis: uroguanylin is a circulating peptide hormone with natriuretic activity. 876 30

The role of brain L-arginine/nitric oxide biochemical pathway in the regulation of drinking behaviour was investigated. Drinking was induced by water deprivation or by intracerebroventricularly (i.c.v.) injected angiotensin II. L-Arginine, the amino-acid precursor of nitric oxide, i.c.v. injected, caused a dose-dependent reduction of the intake of water induced both by water deprivation and i.c.v. angiotensin II (P < 0.001). L-NAME, inhibitor of nitric oxide synthase, reverted L-arginine antidipsogenic effect. L-Arginine, given into the preoptic area (POA) caused a potent antidipsogenic effect (P < 0.001). Either methylene blue (inhibitor of guanylate cyclase activation) or acetylsalicylic acid (ASA), injected into the POA, antagonized the antidipsogenic effect of i.c.v. injected L-arginine. The results indicate that nitric oxide acts as an inhibitory mechanism into the POA and that its antidipsogenic effect requires prostaglandin synthesis.
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PMID:Nitric oxide and drinking behaviour. 889 5

Since nitric oxide (NO) has been widely accepted as a novel neuromodulator, which activates soluble forms of guanylate cyclase to increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, the effect of water-soluble substance in cigarette smoke on cyclic GMP levels were investigated using nerve terminals prepared from rat cerebral cortex. Although the smoke-substance itself failed to affect cyclic GMP levels in the synaptosomes, the smoke-substance significantly inhibited the increases in cyclic GMP levels induced by NO donors. The blocking effect of the smoke-substance was inhibited by concomitant incubation with superoxide dismutase, but not with mannitol. In addition, the effect of smoke-substance was mimicked by products of the xanthine/xanthine oxidase system, but not by nicotine. The effect of smoke-substance was preserved at least 7 days after they were stored at room temperature. Therefore, these results suggest that the smoke-substance may possess long half-lives to produce the radicals which inactivate NO, and to inhibit the increase in cyclic GMP levels in nerve terminals. The interference with NO may explain the part of mechanism in effects of cigarette smoke on neuronal functions.
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PMID:Effects of cigarette smoke on nitric oxide-induced increase in cyclic GMP in nerve terminals of rat cerebral cortex. 891 78


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