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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mammalian plasma-membrane-bound guanylyl cyclase is inhibited by NaCl and this inhibition is dependent on GTP concentrations and independent of the chloride salt type. This chloride inhibition is reversed by GTP analogs such as GTP gamma S, suggesting the involvement of G proteins. When the ability of bacterial toxins to affect this chloride-sensitive guanylyl cyclase was examined, pertussis toxin decreased the basal activity and the chloride sensitivity was greatly reduced. Cholera toxin induced a slight activation of the basal activity, without significant changes in the NaCl inhibition. These data indicate that G proteins regulate the chloride sensitivity of this guanylyl cyclase activity. Another property described here is the ability of ATP and analogs to inhibit the basal activity. However, these nucleotides did not modify the chloride sensitivity of the membrane-bound guanylyl cyclase activity.
...
PMID:G-protein-sensitive guanylyl cyclase activity associated with plasma membranes. 855 11

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 + 5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively. 3. Hypoxic pressure response was significantly increased by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4. Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.
...
PMID:Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat. 864 7

Disruption of guanylyl cyclase-A (GC-A) results in mice displaying an elevated blood pressure, which is not altered by high or low dietary salt. However, atrial natriuretic peptide (ANP), a proposed ligand for GC-A, has been suggested as critical for the maintenance of normal blood pressure during high salt intake. In this report, we show that infusion of ANP results in substantial natriuresis and diuresis in wild-type mice but fails to cause significant changes in sodium excretion or urine output in GC-A-deficient mice. ANP, therefore, appears to signal through GC-A in the kidney. Other natriuretic/diuretic factors could be released from the heart. Therefore, acute volume expansion was used as a means to cause release of granules from the atrium of the heart. That granule release occurred was confirmed by measurements of plasma ANP concentrations, which were markedly elevated in both wild-type and GC-A-null mice. After volume expansion, urine output as well as urinary sodium and cyclic GMP excretion increased rapidly and markedly in wild-type mice, but the rapid increases were abolished in GC-A-deficient animals. These results strongly suggest that natriuretic/diuretic factors released from the heart function exclusively through GC-A.
...
PMID:The heart communicates with the kidney exclusively through the guanylyl cyclase-A receptor: acute handling of sodium and water in response to volume expansion. 865 Feb 46

1. The effects of the sodium salt of the weak acid lactate on tension and intracellular pH (pH1) were studied in rat mesenteric small arteries mounted on a wire myograph. Sodium lactate was substituted iso-osmotically for sodium chloride. 2. At a concentration of 50 mM, both L- and D-stereoisomers of lactate markedly relaxed arteries preconstricted with noradrenaline (NA) within 10 min. The concentration-response relationship for L-lactate showed that the NA contracture was relaxed by 50% at approximately 26 mM. L-Lactate did not, however, relax arteries preconstricted with high-K+(45 mM) solution. 3. L-Lactate did not alter extracellular pH (pHo) but caused a small but significant decrease in pH1, measured using the pH-sensitive fluorochrome, 2',7'-bis(carboxyethyl)-5-(6)-carboxyfluorescein (BCECF). Relaxation to L-lactate was unaffected when this change in pHi was offset by the simultaneous addition of NH4Cl to the solution. 4. Sodium pyruvate (50 mM) caused a significant intracellular acidosis but did not relax arteries preconstricted with NA. 5. L-Lactate-induced relaxations were unaffected by removal of the endothelium or when the synthesis of nitric oxide (NO) was inhibited by 10(-4) M N omega-nitro-L-arginine methyl ester (L-NAME). 6. The potassium channel blockers glibenclamide (10 microM), 4-aminopyridine (3 mM) and tetraethylammonium chloride (10 mM) did not affect L-lactate-induced relaxation in arteries preconstricted with NA. Inhibition of guanylate cyclase with Methylene Blue, or cyclooxgenase with indomethacin, also did not affect relaxation to L-lactate. 7. The Rp stereoisomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), an analogue of cAMP which inhibits competitively stimulation of protein kinase A, reduced significantly L-lactate-induced relaxation at a concentration of 25 microM. Rp-cAMPS also significantly reduced forskolin-induced relaxation of the NA contracture. 8. It is concluded that L-lactate-induced relaxation in this vascular bed is pHi-1 endothelium-, and nitric oxide-independent. It is not mediated by inhibition of voltage-gated Ca2+ channels, opening of K+ channels, prostacylin or cyclic GMP. cAMP may however play a role in L-lactate-induced relaxation.
...
PMID:Mechanism of lactate-induced relaxation of isolated rat mesenteric resistance arteries. 868 76

In the present study, we determined that of the redox forms of nitrogen monoxide, NO-, NO and NO+, only NO significantly activates soluble guanylyl cyclase (GTP pyrophosphate-lyase cyclizing, EC 4.6.1.2). Neither of the NO-donors tested, Angeli's salt (Na2N2O3) or Piloty's acid (C6H5SO2NHOH), caused a change in the guanylyl cyclase activity relative to the basal activity level. Interference by other reaction products was eliminated as a possible explanation for the lack of activation. To the extent that NO+ could be stabilized in aqueous solution, by dissolution of the nitrosonium salt NOPF6 in dry organic solvent prior to addition to the enzyme in buffer, NO+ had no effect on the activity of soluble guanylyl cyclase. The counter-ion, PF6-, had a minimal effect on the enzyme activity and, therefore was, not responsible for the lack of activation by NO+. These observations suggest that NO- is the natural activator of soluble guanylyl cyclase and is reasonably identical with endothelium-derived relaxing factor, the physiological regulator of soluble guanylyl cyclase activity.
...
PMID:Nitric oxide (NO), the only nitrogen monoxide redox form capable of activating soluble guanylyl cyclase. 868 74

Protein folding continues to be an important biophysical topic in molecular biology. We report the parameters for successfully refolding the guanylyl cyclase core of the ANP receptor, an allosteric homodimeric enzyme. Urea was a better chaotropic solvent than guanidine HCl, and physiological salt concentrations and pH were needed for optimal recovery of enzymatic activity. Renaturation was more sensitive to alkaline compared to acidic deviations in solvent conditions. The time course of refolding was sigmoidal producing an enzyme with a specific activity of 16,000 pmol cGMP/min/mg using 60 microM concentration of substrate. Additional factors are described in this unusual case of renaturing an allosteric homodimeric enzyme in vitro.
...
PMID:Refolding parameters for the allosteric homodimeric guanylyl cyclase catalytic core from the atrial natriuretic peptide receptor. 871 20

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.
...
PMID:Circulating and tissue guanylin immunoreactivity in intestinal secretory diarrhoea. 871 28

Cultured pituicytes, derived from the neurohypophysis of adult rats, have previously been reported to change from a non-stellate form to a stellate form when incubated in medium containing a beta-adrenoreceptor agonist. This study was designed to determine whether the same morphological change could be induced by direct activation of adenylate cyclase or of soluble guanylate cyclase. The fraction of stellate cells was normally low (< 0.25) when the pituicytes were incubated (90 min) in a HEPES buffered salt solution (HBSS); most pituicytes had an amorphous protoplasmic appearance. The fraction of stellate cells was significantly increased when pituicytes were incubated in HBSS supplemented with isoproterenol (10 microM) or forskolin (5 microM) or with either of the nitric oxide donors nitroprusside (10-25 microM) and 3-morpholinosydnonimine (SIN-1; 10 microM). The effect of forskolin was mimicked by 8-bromo cyclic AMP, a membrane permeable analog of cyclic AMP, but not by the inactive forskolin analog 1, 9 dideoxyforskolin. The effect of nitroprusside was blocked by methylene blue, an inhibitor of soluble guanylate cyclase, and was mimicked by 8-bromo cyclic GMP, a membrane permeable analog of cyclic GMP. These results demonstrate that activation of adenylate cyclase and also of soluble guanylate cyclase can induce pituicytes to undergo morphological changes in vitro. The data suggest that the activity of both enzymes may be important in control of the plastic relationship that exists between neuronal and glial elements in the neurohypophysis in vivo.
...
PMID:Nitric oxide induces morphological changes in cultured neurohypophysial astrocytes. 873 Jun 57

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.
...
PMID:Salt and water homeostasis: uroguanylin is a circulating peptide hormone with natriuretic activity. 876 30

The aim of the present study was to investigate the effect of Cu(II) ions on soluble guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2; sGC] and to test for a possible physiological role of this putative cofactor of the enzyme [Gerzer et al., FEBS Lett. 132: 71-74, 1981]. CuSO4 was found to inhibit NO-stimulated 5GC with an IC50 of 2.2 +/- 0.3 microM. Virtually complete inhibition of guanosine-3',5'-cyclic monophosphate (cGMP) formation was observed at 10 microM of the copper salt. Presence of CuSO4 (2 microM) did not significantly affect the potency of 2,2-diethyl-1-nitroso-oxyhydrazine (DEA/NO) but did markedly decrease maximal cyclase activity from 3.71 +/- 0.2 mumol cGMP x mg-1 x min-1 to 1.75 +/- 0.2 mumol cGMP x mg-1 x min-1. The nonstimulated enzyme was also sensitive to CuSO4 (IC50 of 6.2 +/- 1.2 microM). Addition of glutathione, which potently complexes Cu(I) ions, induced a pronounced rightward shift of the concentration-response curves for inhibition by CuSO4 of both DEA/NO-stimulated and nonstimulated guanylyl cyclase. The inhibitory effect of CuSO4 was completely antagonized by the specific Cu(I) chelator neocuproine, with a half-maximal effect at 5.9 +/- 0.2 microM. In contrast, the Cu(II) chelator cuprizone and several thiols, which do not form stable Cu(I) complexes, were far less protective. Our results suggest that inhibition of soluble guanylyl cyclase by CuSO4 is unrelated to heme-mediated enzyme stimulation and may arise from the reversible high affinity binding of Cu(I) ions to a site of the protein that is critically involved in enzyme catalysis.
...
PMID:Inhibition of purified soluble guanylyl cyclase by copper ions. 883 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---