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)

The role of the supraspinal nitric oxide (NO)/cyclic GMP system in the development of acute morphine antinociceptive tolerance was investigated by use of the mouse 55 degrees C warm-water tail-flick test. A single intracerebroventricular (i.c.v.) pretreatment of mice with morphine (3 nmol, 140 min before testing) produced an acute antinociceptive tolerance to subsequent i.c.v. doses of morphine, as demonstrated by a 120-fold rightward shift of the morphine dose-response curve. When co-administered with morphine (140 min before testing), the NO synthase inhibitors: N-nitro-L-arginine methyl ester (L-NAME), 3-bromo-7-nitroindazole, 7-nitroindazole and NG-monomethyl-L-arginine, attenuated the development of morphine tolerance. All four NO synthase inhibitors completely blocked the rightward shift of the morphine dose-response curve caused by i.c.v. morphine pretreatment (3 nmol, 140 min before testing). This effect was partially antagonized by L-arginine, but not D-arginine, in a dose-dependent manner. Also, D-NAME did not block the development of tolerance. Like the NO synthase inhibitors, LY-83,583, a guanylyl cyclase inhibitor, blocked the development of tolerance, which suggests that NO acting through the cyclic GMP pathway is involved in the development of acute antinociceptive tolerance. The effects of increased NO production on acute morphine antinociceptive tolerance were also studied. When co-administered with morphine (140 min before testing), neither L-arginine (100 nmol) nor the NO donors, sodium nitroprusside (5 nmol) and isosorbide dinitrate (10 nmol), had any effect on the magnitude of morphine antinociceptive tolerance. These results suggest that NO, acting through the cyclic GMP pathway, mediates the development of acute antinociceptive tolerance, but that NO production does not alter the magnitude of antinociceptive tolerance.
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PMID:The nitric oxide/cyclic GMP system at the supraspinal site is involved in the development of acute morphine antinociceptive tolerance. 943 78

Iodinated atrial natriuretic peptide (ANP) binding sites were examined in the gills and ventral aorta of the adult upstream-migrating lamprey Geotria australis using tissue section autoradiography, in vitro competition analysis and affinity cross-linking, while guanylate cyclase assays were performed on gill membranes of both adult and juvenile lampreys. A partial natriuretic peptide (NP) receptor sequence was amplified using reverse transcription/polymerase chain reaction (RT-PCR). The results indicated that there was specific NP binding to the aortic endothelium and to pillar cell regions in the axial plate and secondary lamellae. In competition studies, 50 % of NP binding was abolished by 4 nmol l-1 rat ANP, 35 nmol l-1 porcine C-type NP (CNP) and 45 nmol l-1 C-ANF (a truncated ANP). Affinity cross-linking followed by SDS-PAGE demonstrated two binding sites at 205 and 65 kDa under non-reducing conditions and at 85 and 65 kDa under reducing conditions. Guanylate cyclase assays demonstrated that, while no NP-stimulated GC activity occurred in adult lampreys, NP-stimulated enhancement of cyclic GMP accumulation was found in juveniles in fresh water and more particularly in salt water. RT-PCR amplified a 471 base pair fragment with 68 % amino acid sequence homology to the eel natriuretic peptide receptor D (NPR-D). This study suggests that NP binding sites in the adult gill and aorta are of an NPR-C/D type, whereas an additional GC-coupled site exists in juveniles.
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PMID:Natriuretic peptide binding sites in the gills of the pouched lamprey Geotria australis. 957 90

Humans are exposed to aluminum from environmental sources and therapeutic treatments. However, aluminum is neurotoxic and is considered a possible etiologic factor in Alzheimer's disease and other neurological disorders. The molecular mechanism of aluminum neurotoxicity is not understood. We tested the effects of aluminum on the glutamate-nitric oxide-cyclic GMP pathway in cultured neurons. Neurons were exposed to 50 microM aluminum in culture medium for short-term (4 h) or long-term (8-14 days) periods, or rats were prenatally exposed, i.e., 3.7% aluminum sulfate in the drinking water, during gestation. Chronic (but not short-term) exposure of neurons to aluminum decreased glutamate-induced activation of nitric oxide synthase by 38% and the formation of cyclic GMP by 77%. The formation of cyclic GMP induced by the nitric oxide-generating agent S-nitroso-N-acetylpenicillamine was reduced by 33%. In neurons from rats prenatally exposed to aluminum but not exposed to it during culture, glutamate-induced formation of cyclic GMP was inhibited by 81%, and activation of nitric oxide synthase was decreased by 85%. The formation of cyclic GMP induced by S-nitroso-N-acetylpenicillamine was not affected. These results indicate that chronic exposure to aluminum impairs glutamate-induced activation of nitric oxide synthase and nitric oxide-induced activation of guanylate cyclase. Impairment of the glutamate-nitric oxide-cyclic GMP pathway in neurons may contribute to aluminum neurotoxicity.
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PMID:Chronic exposure to aluminum impairs neuronal glutamate-nitric oxide-cyclic GMP pathway. 958 Jan 58

We studied the possible role of nitric oxide (NO) in GnRH-induced gonadotropin secretion in the female water frog, Rana esculenta. During pre-reproduction, pre-ovulation, ovulation, post-ovulation, refractory, recovery and hibernation, pituitaries were incubated with medium-alone, GnRH, NO donor (NOd), NO synthase inhibitor (NOSi), cyclic GMP analogue (cGMPa), soluble guanylate cyclase inhibitor (sGCi), GnRH plus NOSi, GnRH plus sGCi, and NOd plus sGCi. Because antisera raised against gonadotropins are not available for this species, we measured these hormones indirectly through their effects on ovarian progesterone secretion. The ovaries were superfused with the pituitaries pre-incubated as reported above. In addition, NOS activity and cGMP levels were determined in the pre-incubated pituitaries. Those pre-incubated with medium-alone and with GnRH increased progesterone secretion during pre-reproduction, pre-ovulation, ovulation and recovery; the increase induced by GnRH was higher than that induced by medium-alone during pre-reproduction, pre-ovulation and recovery. NOd and cGMPa increased progesterone in all considered reproductive phases except ovulation; the increase induced by NOd and cGMP was higher than that induced by medium-alone during pre-reproduction, pre-ovulation and recovery. NOS activity was highest during ovulation and lowest during post-ovulation, refractory and hibernation. GnRH increased NOS activity during pre-reproduction, pre-ovulation and recovery. Cyclic GMP levels were highest during ovulation and lowest during post-ovulation, refractory and hibernation. GnRH increased cGMP levels during pre-reproduction, pre-ovulation and recovery, NOd during all considered reproductive phases. These results suggest that NO mediates basal and GnRH-induced gonadotropin secretion in female Rana esculenta.
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PMID:Nitric oxide mediates gonadotropin-releasing hormone effects on frog pituitary. 968 43

Guanylin and uroguanylin are novel peptides that are first isolated from rat jejunum and opossum urine, respectively. They bind to and activate guanylyl cyclase-C (GC-C) to regulate intestinal and renal fluid and electrolyte transport through the second messenger, cyclic GMP. Heat-stable enterotoxins produced by pathogenic bacteria have close structural similarities to guanylin and uroguanylin, and they use this mimicry to act on GC-C, causing life-threatening secretory diarrhea. Guanylin primarily is restricted to the intestine, whereas uroguanylin is present in the stomach kidney, lung and pancreas in addition to intestine. Guanylin and uroguanylin in the intestine are secreted into the lumen and blood in response to sodium chloride administration. These peptides will function in salt and water transport in the intestine and kidney by luminocrine and/or endocrine actions. Guanylin peptide family links the intestine with the kidney and could play the physiological roles in the control of water and electrolyte balance.
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PMID:[Guanylin family: new intestinal peptides regulating salt and water homeostasis]. 978 Jul 32

1. The involvement of nitric oxide (NO) in the non-adrenergic non-cholinergic inhibitory (NANC-i) neurotransmission was evaluated in guinea-pigs anaesthetized with chloralose-urethane, using a tracheal pouch preparation. 2. The tracheal pouch, a surgically isolated segment of trachea with intact nerve and blood supply, is an in situ method to demonstrate NANC-i response after complete cholinergic and adrenergic blockade using atropine (5 mg kg(-1)) and propranolol (1 mg kg(-1)), respectively. Cervical vagi and sympathetic trunks were isolated and cut cranially. The distal ends of the vagi were positioned on bipolar electrodes for subsequent stimulation with 5 V pulses for 2 ms duration at 15 Hz for a total of 90 s. The relaxation response was measured as a pressure drop (cm of H2O) in the pouch. Each experimental group was composed of six animals. 3. NANC-i responses to two consecutive nerve stimulations at 25 min apart were reproducible. 4. Pouch relaxation responses to electrical nerve stimulations were determined before and after incubation of the pouch with N(omega)-nitro-L-arginine methyl ester (L-NAME; 10(-5) M), a NO synthase (NOS) inhibitor, for 30 min. L-NAME significantly, but not completely, inhibited the NANC-i response of the pouch, suggesting involvement of NO in the NANC-i neurotransmission. 5. The pouch relaxations to vagal stimulations were inhibited significantly after incubation with oxyHb indicating that NO was released. 6. The amount of methaemoglobin (metHb) formed from oxyhaemoglobin (oxyHb) during vagal stimulation was measured by spectrophotometry. Comparison of the values between the control and after nerve stimulation indicated a trend (P = 0.07) toward greater metHb formation in the pouch perfusate after nerve stimulation. 7. NANC-i responses were not significantly inhibited by incubation of the pouch with either of the guanylate cyclase inhibitors, methylene blue or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). However, a trend toward significance (P < or = 0.07) was observed. 8. This study demonstrated that NO is involved in NANC-i neurotransmission. However, the findings did not conclusively support the contention that NO is the sole neurotransmitter of NANC inhibition. It is possible that NO produced relaxation of guinea-pig trachea through a cGMP-independent mechanism.
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PMID:Involvement of nitric oxide in the mediation of NANC inhibitory neurotransmission of guinea-pig trachea. 983 Dec 28

Guanylin is a 15-amino acid peptide, which activates guanylate cyclase (GC) and plays a major role in the regulation of water and electrolyte secretion by intestinal mucosa. The expression of guanylin prohormone has been recently demonstrated in the rat adrenal gland, and this prompted us to investigate whether guanylin, like other peptides secreted by adrenal medulla, affects the function of the adrenal cortex. Autoradiography demonstrated the presence of [125I]guanylin binding sites in the zona glomerulosa (ZG), but not zona fasciculata-reticularis. Guanylin did not change either basal or ACTH-stimulated steroid secretion of dispersed rat adrenocortical cells, but concentration-dependently (from 10(-10) M to 10(-8) M) inhibited aldosterone response of ZG (capsular) cells to both angiotensin-II (ANG-II) and K+. Guanylin (10(-8) M) blocked the aldosterone secretagogue effect of the Ca2+-channel activator BAYK-8644, and the Ca2+-ionophore ionomycin counteracted the inhibitory action of this peptide on the secretory responses of capsular cells to ANG-II and K+. As expected, guanylin did not affect cyclic-AMP release by capsular cells, but evoked a sizeable increase in cyclic-GMP production. Both the inhibitor of GMP synthase decoyinine and the GC-inhibitor LY-83583, although suppressing cyclic-GMP release, did not affect guanylin-evoked inhibition of K+-stimulated aldosterone secretion. Collectively, these findings allow us to conclude that guanylin: i) inhibits aldosterone secretion of rat ZG cells by interfering with the agonist-induced activation of voltage-gated Ca2+-channels, the stimulation of guanylate cyclase conceivably playing a negligible role; and ii) could be included in that group of regulatory peptides, secreted by medullary chromaffin cells, which are able to counteract an exceedingly high aldosterone secretion.
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PMID:Guanylin: a novel regulatory peptide possibly involved in the control of Ca2+-dependent agonist-stimulated aldosterone secretion in rats. 986 86

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 peptides (NP) act as ligands on the guanylyl cyclase family of receptors. The NP binding site on these receptors is extracellular and the guanylyl cyclase and protein kinase domains are intracellular. The guanylyl cyclase receptor catalyzes the synthesis of the second messenger molecule, cGMP, which activates protein kinase. This in turn is involved in the phosphorylation of various ion transport proteins. Ion transport proteins, which are modulated by NP and are thought to underlie the natriuretic and diuretic actions of NP, include: (a) calcium-activated K+ channels; (b) ATP-sensitive K+ channels; (c) inwardly-rectifying K+ channels; (d) outwardly-rectifying K+ channels; (e) L-type Ca2+ channels; (f) Cl- channels including cystic fibrosis transmembrane conductance regulator Cl- channels; (g) Na+- K+ 2Cl- co-transporter; (h) Na+- K+ ATPase; (i) Na+ channels; (j) stretch-activated channels; and (k) water channels. It appears that NP modulate the kinetics, rather than the conductance, of ion channels. Some of these channels, like the Ca2+, ATP-sensitive K+ and stretch-activated channels, are also involved in NP secretion. In addition, the structural properties of the NP, e.g., ovCNP-22 and ovCNP-39, appear to confer on them the ability to form ion channels. These CNP-formed ion channels can modify the trans-membrane signal transduction and second messenger systems underlying NP-induced pathological effects.
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PMID:Role of natriuretic peptides in ion transport mechanisms. 991 94

Uroguanylin, a new natriuretic peptide originally isolated from urine, stimulates the membrane guanylate cyclase C receptor. No information, however, is available on the plasma and urine levels of uroguanylin in nephrotic syndrome (NS), the state associated with sodium and water retention. Using a sensitive radioimmunoassay, we measured the plasma and urine concentrations of immunoreactive (ir-)uroguanylin in NS patients and compared them with those of patients with non-nephrotic glomerulonephritis. Plasma ir-uroguanylin, blood pressure and the cardiothoracic ratio were higher, and urine excretion of ir-uroguanylin was lower in the NS patients. Plasma ir-uroguanylin in the NS patients significantly decreased during remission as compared with findings on admission. There was a significant inverse correlation between the concentration of plasma ir-uroguanylin and that of serum total protein or albumin. Moreover, fluid retention in the NS patients was correlated with the changes in plasma ir-uroguanylin between admission and remission, indicative that the plasma concentration increases with the severity of the nephrotic state. Taking into account its potent natriuretic effect, these findings suggest that uroguanylin may function in the pathophysiological mechanism in NS.
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PMID:Plasma and urine levels of uroguanylin, a new natriuretic peptide, in nephrotic syndrome. 993 51


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