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)

Nitric oxide (.NO) is a recently discovered signaling agent which plays a role in many biological processes such as vasodilation and neuronal synaptic transmission. The only receptor characterized thus far for .NO is the soluble form of guanylate cyclase (sGC). .NO increases the Vmax of sGC by 100-200-fold, probably by interacting with a heme moiety on the enzyme. Although several procedures exist for purifying sGC, these procedures result in preparations with low heme contents. Using a novel procedure, the enzyme has been purified to homogeneity from bovine lung with a heme content of approximately 1 heme/heterodimer. The UV-visible spectrum of the enzyme contains a Soret peak centered at 431 nm and a single broad alpha/beta peak at 555 nm indicative of a 5-coordinate ferrous heme with histidine as the axial ligand. The heme moiety does not bind oxygen but will readily bind .NO to form a 5-coordinate complex or carbon monoxide (CO) to form a 6-coordinate complex. Oxidation of the heme with ferricyanide shifts the Soret to 393 nm, due most likely to the formation of a 5-coordinate ferric heme. In the ferric state, the heme will apparently not bind water but will bind cyanide with reduced affinity compared to methemoglobin and metmyoglobin. Purified enzyme containing 1 heme/heterodimer is activated 130-fold by .NO and 4.4-fold by CO.
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PMID:Soluble guanylate cyclase from bovine lung: activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. 791 35

The lability of the bond between the protein molecule of human platelet guanylate cyclase and heme (the prosthetic group of the enzyme) has been established. It was shown that soluble rat platelet guanylate cyclase exists in these cells originally in a heme-deficient form. The data obtained suggest that in contrast with the generally accepted view, heme is not the prosthetic group of this enzyme. The water-soluble antioxidant carnosine (beta-alanyl-L-histidine) inhibits the guanylate cyclase activation by sodium nitroprusside. This inhibitory effect is caused by carnosine interaction with the guanylate cyclase heme and can be used for evaluating the degree of the heme deficiency of the enzyme. Analysis of the mechanism of guanylate cyclase activation by nitroso complexes of some transient metals (Fe, Co, Cr) differing in the degree of NO oxidation demonstrated that the essential requirement for the realization of the hypotensive effect of these compounds is the activation of guanylate cyclase solely via a heme-dependent mechanism. The ADP-induced aggregation of human platelets (donors) is accompanied by enhanced stimulation of guanylate cyclase by various activators with a simultaneous increase in the intraplatelet cGMP level. This stimulation occurs irrespective of the involvement of the guanylate cyclase heme in the mechanism of enzyme regulation. It is concluded that guanylate cyclase acts via a negative feedback mechanism to control over platelet aggregation and mediates a signal to deaggregation. A hypothetic scheme for the regulatory role of cGMP in platelet aggregation is proposed.
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PMID:[Soluble platelet guanylate cyclase: significance of heme in regulating enzymatic activity and the role of the enzyme in platelet aggregation]. 791 45

A comparative study of the natriuretic-peptide receptor NPR-B was performed by cloning and expressing, in COS-1 cells, the NPR-B receptor subtype from the eel gill which exhibited a strong C-type-natriuretic-peptide (CNP)-induced guanylate cyclase activity. Like other mammalian NPR-B receptors, the eel NPR-B receptor consisted of a ligand-binding extracellular domain, a hydrophobic transmembrane domain, a kinase-like domain and a guanylate cyclase domain. Sequence comparison among the eel and mammalian receptors revealed a relatively low similarity (approximately 44%) in the extracellular domain compared to a very high similarity (approximately 84%) in the cytoplasmic regulatory and catalytic domains. This low similarity allowed identification of the amino acid residues or candidate regions important for the ligand-binding activity. RNase protection analysis of the eel NPR-B mRNA demonstrated that the message was predominantly expressed in the liver and atrium as well as in the gill with moderate-to-small amounts in the brain, ventricle, esophageal sphincter, stomach, posterior intestine and kidney. The high NPR-B mRNA levels in the liver, atrium and gill were found to decrease markedly when eels were transferred from fresh water to seawater and kept there for 2 weeks. Since similar changes are known to occur in the ligand CNP levels when eels are facing osmotic challenges, the CNP/NPR-B system appears to play an important role in their successful adaptation to salinity changes.
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PMID:Cloning and expression of eel natriuretic-peptide receptor B and comparison with its mammalian counterparts. 791 35

Nitrososydnone-5-imines and Thiazole-2-nitrosimines are susceptible to photolytic cleavage of the = N-NO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37 degrees C. Only at higher temp. (70 degrees C) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand NO. and N2O were detected in the head space of the reaction vials when oxygen was excluded. The formation of N2O from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO. was decreased. In the presence of light and thiols soluble guanylate cyclase (s-GC) was stimulated. The results suggest that the nitroxylate anion NO- plays an important role in the stimulation of s-GC.
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PMID:New NO-donors with antithrombotic and vasodilating activities, IV: Chemical reactivity of nitrosimines and its implications for their pharmacologic properties. 791 76

The inner medullary collecting duct (IMCD) is a major target site of atrial natriuretic peptide (ANP) for diuresis and natriuresis, and it is in a hypertonic condition made by the renal countercurrent multiplication system. We investigated the effects of hyperosmolality on ANP-stimulated cGMP generation in IMCD and glomerulus. Hypertonic solutions (490 and 690 mOsm/kg.H2O) were made by adding NaCl or urea to isotonic solution (290 mOsm/kg.H2O). Hypertonicity of 490 mOsm/kg.H2O using NaCl reduced both ANP-stimulated guanylate cyclase activity (from 7.7 +/- 1.1 to 4.1 +/- 0.5 fmol/mm/5 min) and cGMP generation (from 1.35 +/- 0.18 to 0.48 +/- 0.20 fmol/mm/3 min) in IMCD. Hypertonicity of 690 mOsm/kg.H2O using NaCl did not further reduce ANP-stimulated cGMP generation in IMCD. Hypertonicity using urea also inhibited ANP-stimulated guanylate cyclase activity and cGMP generation in IMCD. On the other hand, hypertonicity using NaCl stimulated AVP-stimulated cAMP generation in IMCD, while hypertonicity using urea reduced it. In glomeruli, hyperosmolality of 490 mOsm/kg.H2O using NaCl also reduced ANP-stimulated cGMP generation, and hypertonicity of 690 mOsm/kg.H2O using NaCl further reduced it. In summary, hyperosmolality using NaCl and urea inhibited ANP-sensitive guanylate cyclase activity and cGMP generation both in IMCD and glomeruli. However, the mechanisms at work may be different between NaCl and urea.
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PMID:Effects of hyperosmolality on ANP-stimulated cGMP generation in rat inner medullary collecting duct. 791 40

The effects of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on renal medullary thick ascending limb (mTAL) have not been fully understood. The aim of this study is to examine the second-messenger responses of rat mTAL to ANF, BNP, and CNP. Characterizations of the ANF, BNP, and CNP receptors in mTAL were also performed by radioligand studies. Results showed that ANF and BNP were both capable of eliciting cyclic guanosine monophosphate (cGMP) responses in mTAL. Conversely, no cGMP response was observed upon stimulation by CNP in mTAL. The presence of ANF receptors was demonstrated by radioligand studies. One receptor site was found, and the Kd and maximum binding capacity were 4.0 +/- 0.45 nmol/L and 277.8 +/- 47.7 fmol/mg protein, respectively. BNP receptors were also found in mTAL, and ANF and BNP were sharing the same receptor. On the contrary, no CNP receptor could be shown by radioligand studies. These results suggest that guanylyl cyclase-coupled receptors (atrial natriuretic peptide receptor-A [ANPR-A]) specific for ANF and BNP are present in rat mTAL, while those for CNP (ANPR-B) are absent. ANF and BNP but not CNP act on mTAL to control water excretion.
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PMID:Cyclic guanosine monophosphate responses to atrial natriuretic factor, brain natriuretic peptide, but not C-type natriuretic peptide, and the characterization of their receptors in rat medullary thick ascending limb. 799 Jul 7

1. Drinking was induced in rats by 24 h of water deprivation. Water intake (ml) was evaluated for a 1 h period. 2. NG-nitro-L-arginine methyl ester (L-NAME, 5-10 micrograms, i.c.v., 50-100 ng into the preoptic area (POA)), an inhibitor of nitric oxide (NO) synthase, and methylene blue (50-100 ng into POA), an inhibitor of guanylate cyclase activation, antagonized the inhibition of drinking induced by E. coli endotoxin (LPS, 640 micrograms kg-1, i.v.) and tumour necrosis factor (TNF alpha, 40 ng, i.c.v.) in 24 h water-deprived rats. 3. L-Arginine (25, 50 and 100 ng), the precursor amino acid of NO, but not the stereoisomer D-arginine (100 ng), inhibited drinking induced by water deprivation when injected into the POA 30 min before water presentation (74.4% of inhibition with the highest dose). A dose of 12.5 ng L-arginine into the POA did not exhibit antidipsogenic effects. 4. TNF alpha (20 and 40 ng, i.c.v.; 1.25, 2.5 and 5 ng into the POA) showed a dose-dependent and powerful inhibition of drinking behaviour in water-deprived rats (70.4% and 80.8%, i.c.v. and into POA, with the highest doses, respectively). A dose of 10 ng of TNF alpha given i.c.v. had no effect on the intake of water. 5. LPS and TNF alpha, given at doses (160 micrograms kg-1, i.v. and 10 ng, i.c.v., respectively) that did not influence drinking in water-deprived rats, exhibited a strong antidipsogenic effect in water-deprived rats treated with a dose of L-arginine (12.5 ng, into the POA) which did not modify drinking by itself. (LPS + L-arginine:53.6% of inhibition; TNFalpha + L-arginine: 52.0% of inhibition).6. These results suggest that NO into the POA: (1) acts as an inhibitory mechanism on thirst and (2)plays a role in the antidipsogenic effect of LPS and TNFalpha.
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PMID:Mediation by nitric oxide formation in the preoptic area of endotoxin and tumour necrosis factor-induced inhibition of water intake in the rat. 803 19

The natriuretic peptide family of proteins acts through two distinct classes of receptors that signal through entirely different mechanisms. The elucidation of the structure of the guanylate cyclase-containing receptor proteins has provided a better understanding of the mechanisms by which the natriuretic peptides regulate diverse functions of salt and water balance, in conjunction with other vasoactive peptides. A second receptor class was named for the originally described function of this protein to clear the natriuretic peptides from plasma. The mechanism of signaling for the natriuretic peptide clearance receptor is not firmly established. All known members of the natriuretic peptide family bind to, and can theoretically act through, the clearance receptor. This review summarizes the known features of the natriuretic peptide clearance receptor, a protein that contains extracellular and transmembrane domains and a short cytoplasmic segment. Recent studies have pointed to new and potentially important functions for this protein in mediating the actions of the natriuretic peptides.
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PMID:Natriuretic peptide C-receptor: more than a clearance receptor. 809 74

To elucidate the sequence of events between the release of neurotransmitters and cavernous smooth muscle relaxation in erection, we studied the role of the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) systems. In a well-established simian model, the effects of specific agonists and antagonists of the intracellular sequence for smooth muscle relaxation and potassium channel openers on the intracavernous pressure were examined. Sodium nitroprusside (10(-3) M), a nitric oxide releaser and thus a stimulant of the cGMP system, caused an increase in the intracavernous pressure from 82 to 115 cm H2O for 7 to 19 min and penile diameter from 24.8 +/- 2.28 to 43 +/- 4.87 mm. When nitroprusside was injected after methylene blue (10(-3) M), a specific antagonist of the enzyme guanylate cyclase, intracavernous pressure rise decreased significantly, but cromakalin, a potassium channel opener, provoked excellent increases after the block. A smaller dose of sodium nitroprusside (10(-4) M) caused an increase in intracavernous pressure from 35 to 85 cm H2O for 7 to 11.5 min. When nitroprusside was injected after zaprinast, a phosphodiesterase inhibitor, the increase in pressure ranged from 80 to 116 cm H2O for 15 to 30 min. Prostaglandin E1, an activator of the cAMP system, caused an increase in the intracavernous pressure of 20-80 cm H2O for 5 to 10 min, and an increase in penile diameter from 25 +/- 2.22 to 35 +/- 3.48 mm. The erectile response to PGE1, but not to cromakalin, was nearly abolished by ethylmaleimide, an adenylate cyclase blocker. The response to nitroprusside was significantly greater (P < 0.05) than to PGE1. Both systems, cAMP and cGMP, may be involved in cavernous smooth muscle relaxation, and cGMP is probably the predominant intracellular second messenger in penile erection in monkeys. Stimulants of the cGMP system, such as nitric oxide releasers, could represent a more physiological and effective approach in the treatment of erectile dysfunction.
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PMID:Intracellular mechanism of penile erection in monkeys. 815 77

Guanylin, a bioactive peptide, has recently been isolated from the intestine; this peptide activates intestinal guanylate cyclase (i.e., guanylate cyclase C) and thus is potentially involved in the regulation of water/electrolyte transport in the gastrointestinal mucosa. As yet, the cells involved in synthesis, storage, or secretion of guanylin have not been identified by immunocytochemistry. We raised antisera against guanylin and investigated the entire gastrointestinal tract of guinea pigs by light and electron microscopical immunocytochemistry. Extracts of various intestinal segments and plasma analyzed on a Western blot revealed a peptide band corresponding to the molecular mass of guanylin. Localization studies in the entire digestive tract showed that guanylin is exclusively confined to enterochromaffin (EC) cells. Remarkably, most EC cells contacted the gut lumen by cell processes that were highly immunoreactive for guanylin. In addition to the well known secretion in an endocrine fashion, EC cells by circumstantial evidence may release guanylin into the gut lumen to activate guanylate cyclase C that is immediately located on the brush border of adjacent enterocytes. The unique localization of guanylin in EC cells may indicate that these cells are involved in the regulation of fluid secretion in the gastrointestinal mucous membrane.
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PMID:Enterochromaffin cells of the digestive system: cellular source of guanylin, a guanylate cyclase-activating peptide. 815 83


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