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)

Uroguanylin and guanylin are newly discovered endogenous heat-stable peptides that bind to and activate a membrane bound guanylyl cyclase signaling receptor (termed guanylyl cyclase C; GC-C). These peptides are not only found in blood but are secreted into the lumen of the intestine and effect a net secretion of electrolytes (Na+, K+, Cl-, HCO3-) and fluid into the intestine via a cyclic guanosine-3', 5'-monophosphate (cGMP) mechanism. GC-C is also the receptor for Escherichia coli heat-stable enterotoxin (STa) and activation by STa results in a diarrheal illness. Employing mouse renal in vivo models, we have demonstrated that uroguanylin, guanylin, and STa elicit natriuretic, kaliuretic, and diuretic effects. These biological responses are time- and dose-dependent. Maximum natriuretic and kaliuretic effects are observed within 30-40 min following infusion with pharmacological doses of the peptides in a sealed-urethra mouse model. Our mouse renal clearance model confirms these results and shows significant natriuresis following a constant infusion of uroguanylin for 30 min, while the glomerular filtration rate, plasma creatinine, urine osmolality, heart rate, and blood pressure remain constant. These data suggest the peptides act through tubular transport mechanisms. Consistent with a tubular mechanism, messenger RNA-differential display PCR of kidney RNA extracted from vehicle- and uroguanylin-treated mice show the message for the Na+/K+ ATPase gamma-subunit is down-regulated. Interestingly, GC-C knockout mice (Gucy2c -/-) also exhibit significant uroguanylin-induced natriuresis and kaliuresis in vivo, suggesting the presence of an alternate receptor signaling mechanism in the kidney. Thus, uroguanylin and guanylin seem to serve as intestinal and renal natriuretic peptide-hormones influencing salt and water transport in the kidney through GC-C dependent and independent pathways. Furthermore, our recent clinical probe study has revealed a 70-fold increase in levels of urinary uroguanylin in patients with congestive heart failure. In conclusion, our studies support the concept that uroguanylin and guanylin are endogenous effector peptides involved in regulating body salt and water homeostasis.
...
PMID:Renal effects of uroguanylin and guanylin in vivo. 1055 34

Guanylin and uroguanylin are intestinal peptides that stimulate guanylate cyclase C and cause chloride secretion. These peptides show topological instability due to two disulfide bonds. The disulfide bonds were reduced and S-carboxymethylated to cleave the bonds and obtain stable and sole derivatives. We established a new and reliable RIA system for the stable derivatives from both peptides. With the use of this system, the response of the peptides to salt loading of the rat small intestine was evaluated. The lumen of the small intestines of Sprague-Dawley rats was perfused in vivo with Krebs-Ringer solution containing different concentrations of salt or mannitol. Mature guanylin, proguanylin, and mature uroguanylin were found in the perfusate in the basal state. The highest salt loading (200 mM NaCl for 20 min) increased the guanylin secretion about threefold (1.9 +/- 0.2 vs. 5.4 +/- 0.5 pmol/min), with the effect lasting for 60 min. The uroguanylin secretion was less affected. Hyperosmolar mannitol also caused a significant but smaller increase of guanylin secretion. Increased guanylin could lead to increased salt and water secretion of the intestine; thus members of the guanylin family have potential roles in the regulation of water and salt metabolism in the small intestine.
...
PMID:Marked increase of guanylin secretion in response to salt loading in the rat small intestine. 1056 1

We studied the modes of activation of the salt-secreting rectal gland of the spiny dogfish, Squalus acanthias, by the native cardiac peptide CNP. The stimulatory action of CNP in isolated perfused glands is inhibited by 10 mM procaine, presumably by blocking release of vasoactive intestinal peptide (VIP) from nerves. Procaine reduces the slope of the dose-response curve of human CNP and that of shark CNP (each P < 0.0001). CNP increases short-circuit current in cultured rectal gland cells from 4.8 +/- 1.6 to 27.0 +/- 7.8 microA/cm2. It also stimulates the secretion of chloride in isolated perfused glands in the presence of 10 mM procaine from 72 +/- 31 to 652 +/- 173 microeq. h(-1). g(-1). These results suggest that CNP has a direct cellular action not mediated by the neural release of VIP. The residual stimulation of perfused glands in the presence of procaine was almost completely inhibited by staurosporine [10 nM; an inhibitor of protein kinase C (PKC)] from 652 +/- 173 to 237 +/- 61 microeq. h(-1). g(-1). Although CNP stimulates guanylyl cyclase in shark rectal gland, chloride secretion of perfused glands was not elicited by 8-bromoadenosine-cGMP (8-BrcGMP) alone nor by the activator of PKC phorbol ester. The combination of PKC activation and 8-BrcGMP infusion, however, stimulated chloride secretion in perfused glands from 94 +/- 30 to 506 +/- 61 microeq. h(-1). g(-1), a level comparable to that observed in glands blocked with procaine. Several parallel pathways appear to be synergistic in activating chloride secretion stimulated by CNP in the rectal gland.
...
PMID:Mode of activation of salt secretion by C-type natriuretic peptide in the shark rectal gland. 1060 Sep 20

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.
...
PMID:B-type natriuretic peptide receptor expression and activity are hormonally regulated in rat ovarian cells. 1065 Sep 35

The guanylin family of cGMP-regulating peptides has three subclasses of peptides containing either three intramolecular disulfides found in bacterial heat-stable enterotoxins (ST), or two disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin. These small, heat-stable peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity. Two receptor GC signaling molecules have been identified that are highly expressed in the intestine (GC-C) and/or the kidney (OK-GC) and are selectively activated by the guanylin peptides. Stimulation of cGMP production in renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis. Activation of GC-C receptors in target cells of intestinal mucosa markedly stimulates the transepithelial secretion of Cl(-) and HCO(-)/(3), causing enhanced secretion of fluid and electrolytes into the intestinal lumen. Bacterial ST peptides act as mimics of guanylin and uroguanylin in the intestine, which provide a cellular mechanism underlying the diarrhea caused by ST-secreting strains of Escherichia coli. Uroguanylin and guanylin may participate in a novel endocrine axis linking the digestive system and kidney as a physiological mechanism that influences Na(+) homeostasis. Guanylin, uroguanylin, and/or lymphoguanylin may also serve within intrarenal signaling pathways controlling cGMP production in renal target cells. Thus we propose that guanylin regulatory peptides participate in a complex multifactorial biological process that evolved to regulate the urinary excretion of NaCl when dietary salt levels exceed the body's physiological requirements. This highly integrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess NaCl in the urine. Uroguanylin, in particular, may be a prototypical "intestinal natriuretic hormone."
...
PMID:Guanylin peptides: renal actions mediated by cyclic GMP. 1066 22

Disruption of the atrial natriuretic peptide (ANP) receptor [guanylyl cyclase-A (GC-A)] gene yields mice with a salt-resistant form of hypertension, raising fundamental questions on the role of ANP in acute regulation of the kidney. Here, we show that water intake, food consumption, stool weight, urine volume, and sodium excretion are not significantly different between wild-type and GC-A null mice on standard rodent chow (0.7% NaCl) or a high-salt diet (8% NaCl). In conscious mice with an indwelling catheter, the infusion of a physiological saline solution containing 4% BSA resulted in a marked natriuresis/diuresis in wild-type mice but no response in GC-A null animals. When physiological saline was given by gavage, however, the kidney response of wild-type and null mice was equivalent, raising the possibility that the gastrointestinal tract can directly regulate kidney function. However, administration of 0.9% saline through an intraperitoneal route also resulted in equal kidney responses in wild-type and null mice. When 0.9% NaCl lacking protein was infused i.v., wild-type and null mice both responded at the kidney level. Thus, GC-A appears dispensable for regulation of sodium/water excretion in response to changes in dietary sodium concentration, but likely becomes critical in volume expansions where the isooncotic pressure remains constant, such as head-out immersion or the initial and correctable stages of congestive heart failure.
...
PMID:A genetic model defines the importance of the atrial natriuretic peptide receptor (guanylyl cyclase-A) in the regulation of kidney function. 1076 Mar 3

The endocrine function of the heart is to secrete Atrial and Brain natriuretic -peptides (ANP and BNP). These peptides are biologically active via particulate guanylate cyclases which generate cyclic GMP, the second intracellular messenger. A polysaccharide antagonist, HS-142-1 has been recently described by a Japanese Group. Cyclic GMP is partly secreted from the target cells into the extra cellular medium in which its accumulation is proportional to the concentration of the natriuretic peptide. Neutral Endopeptidase (NEP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides. NEP is absent in plasma but present on the surface of endothelial and smooth muscle cells. NEP is mainly expressed at the apical pole of the epithelial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is associated with the oversecretion of natriuretic peptides. This chronic phenomenon involves the recruitment of all the cardiac myocytes to express natriuretic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic peptides correlate with the level of the -hemodynamic stress. Therefore the plasma levels of natriuretic peptides are good pronostic markers in both experimental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also -correlated with the plasma and urinary levels of cyclic GMP. The plasma level of -cyclic GMP is correlated with the endothelial concentration of cyclic GMP but not with the cyclic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells and is related to particulate guanylate cyclase activity. In contrast natriuretic peptides do not modulate vascular wall cyclic GMP content. The natriuretic action of ANP is probably due to the interaction of the filtered peptide with the particulate guanylate cyclase at the apical pole of the epithelial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urinary compartment. It is also by a urinary pathway via the macula densa that ANP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP correlate with the degree of salt retention in congestive heart failure, provides evidence for chronic desensitization of the system. An up-regulation of Na(+), K(+), 2Cl(-) expression associated with experimental congestive heart failure has recently been shown. Similarly, a modulation of the different sodium transporter systems along the nephron could be one of the counter-regulations leading to desensitization to natriuretic peptides. In conclusion, natriuretic peptides are true endocrine peptides, secreted by the heart, transported in the plasma, filtered by the glomeruli and active at the nephron level. The molecular effector of ANP and cyclic GMP in the epithelial cells is probably the G-kinase II, isoform phosphorylating the cystic fibrosis transmembrane conductance regulator (CFTR). The exact mechanism of desensitization remains to be elucidated.
...
PMID:[Functional compartmentation of the endocrine action of cardiac natriuretic peptides]. 1079 May 90

Natriuretic peptides exist in the fishes as a family of structurally-related isohormones including atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP) and ventricular natriuretic peptide (VNP); to date, brain natriuretic peptide (or B-type natriuretic peptide, BNP) has not been definitively identified in the fishes. Based on nucleotide and amino acid sequence similarity, the natriuretic peptide family of isohormones may have evolved from a neuromodulatory, CNP-like brain peptide. The primary sites of synthesis for the circulating hormones are the heart and brain; additional extracardiac and extracranial sites, including the intestine, synthesize and release natriuretic peptides locally for paracrine regulation of various physiological functions. Membrane-bound, guanylyl cyclase-coupled natriuretic peptide receptors (A- and B-types) are generally implicated in mediating natriuretic peptide effects via the production of cyclic GMP as the intracellular messenger. C- and D-type natriuretic peptide receptors lacking the guanylyl cyclase domain may influence target cell function through G(i) protein-coupled inhibition of membrane adenylyl cyclase activity, and they likely also act as clearance receptors for circulating hormone. In the few systems examined using homologous or piscine reagents, differential receptor binding and tissue responsiveness to specific natriuretic peptide isohormones is demonstrated. Similar to their acute physiological effects in mammals, natriuretic peptides are vasorelaxant in all fishes examined. In contrast to mammals, where natriuretic peptides act through natriuresis and diuresis to bring about long-term reductions in blood volume and blood pressure, in fishes the primary action appears to be the extrusion of excess salt at the gills and rectal gland, and the limiting of drinking-coupled salt uptake by the alimentary system. In teleosts, both hypernatremia and hypervolemia are effective stimuli for cardiac secretion of natriuretic peptides; in the elasmobranchs, hypervolemia is the predominant physiological stimulus for secretion. Natriuretic peptides may be seawater-adapting hormones with appropriate target organs including the gills, rectal gland, kidney, and intestine, with each regulated via, predominantly, either A- or B-type (or C- or D-type?) natriuretic peptide receptors. Natriuretic peptides act both directly on ion-transporting cells of osmoregulatory tissues, and indirectly through increased vascular flow to osmoregulatory tissues, through inhibition of drinking, and through effects on other endocrine systems.
...
PMID:Natriuretic peptides in fish physiology. 1082 90

Intracellular Ca(2+) mobilization and release into mammal CSF plays a fundamental role in the etiogenesis of fever induced by the proinflammatory cytokine interleukin-1beta (IL-1beta) and other pyrogens. The source and mechanism of IL-1beta-induced intracellular Ca(2+) mobilization was investigated using two experimental models. IL-1beta (10 ng/ml) treatment of rat striatal slices preloaded with (45)Ca(2+) elicited a delayed (30 min) and sustained increase (125-150%) in spontaneous (45)Ca(2+) release that was potentiated by l-arginine (300 microm) and counteracted by N-omega-nitro-l-arginine methyl ester (l-NAME) (1 and 3 mm). The nitric oxide (NO) donors diethylamine/NO complex (sodium salt) (0.3 and 1 mm) and spermine/NO (0.1 and 0.3 mm) mimicked the effect of IL-1beta on Ca(2+) release. IL-1beta stimulated tissue cGMP concentration, and dibutyryl cGMP enhanced Ca(2+) release. The guanyl cyclase inhibitors 1H-[1,2, 4]oxadiazole[4,3-a] quinoxalin-1-one (100 microm) and 6-[phenylamino]-5,8 quinolinedione (50 microm) counteracted Ca(2+) release induced by 2.5 but not 10 ng/ml IL-1beta. Ruthenium red (50 microm) and, to a lesser extent, heparin (3 mg/ml) antagonized IL-1beta-induced Ca(2+) release, and both compounds administered together completely abolished this response. Similar results were obtained in human astrocytoma cells in which IL-1beta elicited a delayed (30 min) increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) (402 +/- 71.2% of baseline), which was abolished by 1 mm l-NAME. These data indicate that the NO/cGMP-signaling pathway is part of the intracellular mechanism transducing IL-1beta-evoked Ca(2+) mobilization in glial and striatal cells and that the ryanodine and the inositol-(1,4,5)-trisphosphate-sensitive Ca(2+) stores are involved.
...
PMID:Nitric oxide modulation of interleukin-1[beta]-evoked intracellular Ca2+ release in human astrocytoma U-373 MG cells and brain striatal slices. 1112 73

Nitric oxide (NO) is a potent neuromodulator in the CNS and PNS. At the frog neuromuscular junction (nmj), exogenous application of NO reduces neurotransmitter release, and NO synthases (NOSs), the enzymes producing NO, are present at this synapse. This work aimed at studying the molecular mechanisms by which NO modulates synaptic efficacy at the nmj using electrophysiological recordings and Ca(2+)-imaging techniques. Bath application of the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside decreased end plate potential (EPP) amplitude as well as the frequency of miniature EPPs but not their amplitude. Ca(2+) responses elicited in presynaptic terminals by single action potentials were unaffected by NO, but responses evoked by a short train of stimuli were increased. Tonic endogenous production of NO was observed as suggested by the increase in EPP amplitude by bath application of the NO scavenger hemoglobin and the neuronal NOS inhibitor 3-bromo-7-nitroindazole sodium salt. A soluble guanylate cyclase inhibitor, 6-anilino-5,8-quinolinedione (LY-83583), increased EPP amplitude and occluded the effects of the NO donor, suggesting that NO acts via a cGMP-dependent mechanism. High-frequency-induced depression was reduced in the presence of the NO scavenger but not by LY-83583. However, adenosine-induced depression was significantly reduced after bath perfusion of SNAP and in the presence of LY-83583. Our results indicate that NO regulates transmitter release and adenosine-induced depression via a cGMP-dependent mechanism that occurs after Ca(2+) entry and that high-frequency-induced synaptic depression is regulated by NO in a cGMP-independent manner.
...
PMID:Differential frequency-dependent regulation of transmitter release by endogenous nitric oxide at the amphibian neuromuscular synapse. 1116 Mar 78


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

---