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)

Atrial natriuretic peptide (ANP) binds to the guanylyl cyclase-A (GC-A) receptor found in tissues such as the kidney and adrenal gland, resulting in marked elevations of the intracellular signaling molecule, cGMP. Here, GC-A is shown to exist as a phosphoprotein when expressed in human embryonic 293 cells. The 32P is principally associated with phosphoserine, with only trace amounts of phosphothreonine. The addition of ANP causes a time-dependent dephosphorylation of the receptor, as well as desensitization, which is not due to an ANP-mediated decrease in the amount of receptor protein. The mobility of GC-A on sodium dodecyl sulfate-polyacrylamide gel electrophoresis increases after treatment of cells with ANP, and protein phosphatase 2A induces the same mobility shift. The protein phosphatase also catalyzes dephosphorylation of GC-A, and this is directly correlated with decreases in ANP-stimulatable guanylyl cyclase activity. Okadaic acid, an inhibitor of protein phosphatase 2A, blocks both the dephosphorylation and the desensitization. Therefore, in contrast to many other cell surface receptors, GC-A is desensitized by ligand-induced dephosphorylation.
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PMID:Dephosphorylation of the guanylyl cyclase-A receptor causes desensitization. 135 76

Previously we showed that atrial natriuretic factor (ANF) decreases cardiac cell volume by inhibiting ion uptake by Na+/K+/2Cl- cotransport. Digital video microscopy was used to study the role of guanosine 3',5'-monophosphate (cGMP) in this process in rabbit ventricular myocytes. Each cell served as its own control, and relative cell volumes (volume(test)/volume(control)) were determined. Exposure to 10 microM 8-bromo-cGMP (8-Br-cGMP) reversibly decreased cell volume to 0.892 +/- 0.007; the ED50 was 0.77 +/- 0.33 microM. Activating guanylate cyclase with 100 microM sodium nitroprusside also decreased cell volume to 0.889 +/- 0.009. In contrast, 8-bromo-adenosine 3',5'-monophosphate (8-Br-AMP; 0.01-100 microM) neither altered cell volume directly nor modified the response to 8-Br-cGMP. The idea that cGMP decreases cell volume by inhibiting Na+/K+/2Cl- cotransport was tested by blocking the cotransporter with 10 microM bumetanide (BUM) and removing the transported ions. After BUM treatment, 10 microM 8-Br-cGMP failed to decrease cell volume. Replacement of Na+ with N-methyl-D-glucamine or Cl- with methanesulfonate also prevented 8-Br-cGMP from shrinking cells. The data suggest that 8-Br-cGMP, like ANF, decreases ventricular cell volume by inhibiting Na+/K+/2Cl-cotransport. Evidence that ANF modulates cell volume via cGMP was also obtained. Pretreatment with 10 microM 8-Br-cGMP prevented the effect of 1 microM ANF on cell volume, and ANF suppressed 8-Br-cGMP-induced cell shrinkage. Inhibiting guanylate cyclase with the quinolinedione LY83583 (10 microM) diminished ANF-induced cell shrinkage, and inhibiting cGMP-specific phosphodiesterase with M&B22948 (Zaprinast; 100 microM) amplified the volume decrease caused by a low dose of ANF (0.01 microM) approximately fivefold. In contrast, neither 100 microM 8-Br-cAMP nor 50 microM forskolin affected the response to ANF. The effects of ANF, LY83583, and M&B29948 on cGMP levels in isolated ventricular myocytes were confirmed by 125I-cGMP radioimmunoassay. These data argue that ANF shrinks cardiac cells by increasing intracellular cGMP, thereby inhibiting Na+/K+/2Cl- cotransport. Basal cGMP levels also appear to modulate cell volume.
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PMID:Modulation of rabbit ventricular cell volume and Na+/K+/2Cl- cotransport by cGMP and atrial natriuretic factor. 135 6

Atrial natriuretic peptide (ANP) inhibits aldosterone secretion evoked by its physiological secretagogues by a mechanism(s) likely to involve intracellular messengers. When one examines the results of various investigations so far, this premise, although not definitive yet, seems to be supported. Therefore a brief perspective on the cellular messengers of the various secretagogues is provided before the inquiry into the possible mechanism of action of ANP. The receptors of ANP in the adrenal cells have been identified and characterized. ANP inhibits adenylate cyclase in various tissues through an inhibitory G protein, which appears to explain in part the inhibitory effect of ANP on adrenocorticotropin-induced aldosterone secretion. However, there could be other possible effects of ANP as discussed. ANP probably inhibits aldosterone secretion evoked by angiotensin II and potassium by interfering with the appropriate changes in calcium flux and cell calcium concentration, concomitants of stimulation by these secretagogues. The potential modes of these effects are probed. The role of guanosine 3',5'-cyclic monophosphate, which is increased by receptor activation of guanylate cyclase by ANP and is thought to play a major role in the biological effects of ANP in some other tissues, remains controversial in the aldosterone-lowering effect of ANP, and this is also discussed extensively in this review.
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PMID:Atrial natriuretic peptide-induced inhibition of aldosterone secretion: a quest for mediator(s) 135 32

The cellular mechanisms through which halothane dilates blood vessels remain largely unknown. The present studies were designed to determine the effects of 0.59 and 0.9 mM halothane (equivalent to 2.0% and 3.0%, respectively) on tissue cyclic guanosine 3,5-monophosphate (cGMP) level and guanylate cyclase enzyme activity in canine middle cerebral arteries. Rings of cerebral arteries preconstricted with 5-hydroxytryptamine (0.2 microM) were exposed for 15 min to low or high concentrations of halothane or for 5 min to sodium nitroprusside (50 microM). The vessels were instantaneously frozen by immersing them in liquid N2; they then were homogenized, and the tissue cGMP levels were determined using radioimmunoassay. Halothane produced 2.23 +/- 0.44- and 4.47 +/- 0.87-fold increases in tissue cGMP levels over control at 0.59 and 0.9 mM, respectively. Sodium nitroprusside, a nitrovasodilator, also increased the tissue cGMP level 7.80 +/- 1.36-fold over the control value. To understand better the mechanisms of halothane-induced increase of tissue cGMP level, the effects of this anesthetic agent on guanylate cyclase enzyme activity were examined. Halothane, unlike sodium nitroprusside, did not modulate the activity of the soluble guanylate cyclase enzyme. However, halothane (1.0 mM), like atrial natriuretic factor (5 microM), stimulated the particulate guanylate cyclase enzyme activity. LY-83583 (6-anilino-5,8-quinolinedione, 10 microM), an agent that inhibits soluble guanylate cyclase activity, significantly reduced the response of the vessels to calcium ionophore (A23187, 0.4 microM), an endothelium-dependent vasodilator, without producing a significant effect on halothane-induced vasodilation. These results suggest that halothane-induced vasodilation of cerebral blood vessels is partly mediated by an increase in tissue cGMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of guanylate cyclase-cGMP systems in halothane-induced vasodilation in canine cerebral arteries. 809 27

Atrial natriuretic factor (ANF) is a peptide hormone from the heart atrium with potent natriuretic and vasorelaxant activities. The natriuretic activity of ANF is, in part, mediated through the adrenal gland, where binding of ANF to the 130-kDa ANF receptor causes suppression of aldosterone secretion. Incubation of bovine adrenal membranes at pH < 5.6 caused a rapid and spontaneous cleavage of the 130-kDa ANF receptor, yielding a 65-kDa polypeptide that could be detected by photoaffinity labeling by 125I-labeled N alpha 4-azidobenzoyl-ANF(4-28) followed by SDS/PAGE under reducing conditions. Within 20 min of incubation at pH 4.0, essentially all the 130-kDa receptor was converted to a 65-kDa ANF binding protein. This cleavage reaction was completely inhibited by inclusion of 5 mM EDTA. When SDS/PAGE was carried out under non-reducing conditions, the apparent size of the ANF receptor remained unchanged at 130 kDa, indicating that the 65-kDa ANF-binding fragment was still linked to the remaining part(s) of the receptor polypeptide through a disulfide bond(s). The disappearance of the 130-kDa receptor was accompanied by a parallel decrease in guanylate cyclase activity in the membranes. Inclusion of EDTA in the incubation not only prevented cleavage of the 130-kDa receptor, but also protected guanylate cyclase activity, indicating that proteolysis, but not the physical effects of the acidic pH, causes inactivation of guanylate cyclase. The 130-kDa ANF receptor in adrenal membranes was competitively protected from photoaffinity labeling by ANF(1-28) or ANF(4-28), but not by atriopeptin I [ANF(5-25)] or C-ANF [des-(18-22)-ANF(4-23)-NH2]. On the contrary, the 65-kDa ANF-binding fragment generated after incubation at pH 4.0 was protected from labeling by any of the above peptides, indicating broader binding specificity. After incubation in the presence of EDTA, the 130-kDa ANF receptor, which was protected from proteolysis, retained binding specificity identical to that of the 130-kDa receptor in untreated membranes. The results indicate that the broadening of selectivity is caused by cleavage, but not by the physical effect of acidic pH. Spontaneous proteolysis of ANF receptor by an endogenous metalloendopeptidase, occurring with concomitant inactivation of guanylate cyclase activity and broadening of ligand-binding selectivity, may be responsible for the generation of low-molecular-mass receptors found in the adrenal gland and other target organs of ANF. The proteolytic process may play a role in desensitization or down-regulation of the ANF receptor.
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PMID:Proteolytic cleavage of atrial natriuretic factor receptor in bovine adrenal membranes by endogenous metalloendopeptidase. Effects on guanylate cyclase activity and ligand-binding specificity. 135 9

Formycin A triphosphate (FTP), a fluorescent analog of ATP, slightly increased basal guanylate cyclase activity, but significantly potentiated guanylate cyclase activity stimulated by atrial natriuretic factor (ANF) in rat lung membranes. FTP potentiated ANF-stimulated guanylate cyclase activity with an EC50 at about 90 microM and inhibited ATP-stimulated guanylate cyclase activity with an IC50 at about 100 microM. These results indicate that FTP binds more tightly than ATP for the same binding site. Therefore, FTP would be an excellent tool for studying the ATP binding site.
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PMID:Formycin triphosphate as a probe for the ATP binding site involved in the activation of guanylate cyclase. 135 64

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.
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PMID:Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. 137 15

Coculture of endothelial cells with atrial cells (R. A. Lew and A. J. Baertschi. Biochem. Biophys. Res. Commun. 163: 701-709, 1989) increased atrial natriuretic factor (ANF) release to 205 +/- 15% (n = 33 experiments) of basal secretion (2.02 +/- 0.33 ng/ml). Stimulation of ANF release by endothelial cells was significantly reduced (P < 0.05) by addition of the calcium channel antagonist nicardipine (Nic, 100 nM; by 69 +/- 4%), the guanylate cyclase activator sodium nitroprusside (SNP, 1 microM; by 97 +/- 27%), or acetylcholine (ACh, 10 microM; by 55 +/- 13%). Endothelial cell-conditioned medium elicited a 62 +/- 10% (n = 10) increase in ANF release. Rat and porcine endothelin (0.1-100 nM) each elicited a dose-dependent increase in ANF release [up to 84 +/- 14% (n = 18) over baseline]. The activity of conditioned medium was not affected by heat or trypsin treatment, but was significantly reduced by addition of Nic or SNP and was attenuated by ACh. Stimulation of ANF by 1 nM synthetic rat or porcine endothelin was also unaffected by heat or trypsin but was significantly reduced by Nic, SNP, and ACh. Addition of endothelin-specific antiserum abolished the ANF stimulatory activity of endothelial cell-conditioned medium. Neither inhibition of superoxide anion by superoxide dismutase nor inhibition of endothelium-derived nitric oxide production by NG-monomethyl-L-arginine affected the ANF release from coculture. Thus endothelial cells release a heat-stable, diffusible ANF stimulatory factor, which is not endothelium-derived relaxing factor or superoxide anion but is biologically and immunologically similar to endothelin.
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PMID:Endothelium-dependent ANF secretion in vitro. 141 54

Atrial natriuretic factor (ANF) is released from the cardiac atrium in response to stretch and acts through receptors to cause an increase in urinary flow and sodium excretion, vasodilatation, and a reduction in blood volume. Recently, two new natriuretic peptides, brain natriuretic peptide (BNP) and C-type natriuretic peptide (C-typeNP), have been isolated, and three different natriuretic peptide receptors have been identified. Two of the receptors, ANP-RGC(A) and ANP-RGC(B), mediate biologic actions. The natural ligand of ANP-RGC(A) is ANF, whereas that of ANP-RGC(B) is C-typeNP. In view of clear differences in ligand specificity and tissue distribution of these receptors, it has been proposed that ANF and its receptor, ANP-RGC(A), and C-typeNP and its receptor, ANP-RGC(B), represent two distinct natriuretic peptide regulatory systems. Whether a separate system exists that incorporates BNP awaits clarification of its natural receptor that mediates a biologic action. The third receptor, ANP-Rc, binds all three natriuretic peptides. Its messenger RNA lacks the guanylyl cyclase sequence present in the mRNA of the other natriuretic peptide receptors, suggesting that the principal function of ANP-Rc is to remove natriuretic peptides from the circulation, that is, to regulate plasma levels of the natriuretic peptides. However, ANP-Rc may also mediate a biologic effect. These findings raise several intriguing questions about the functional role of this family of natriuretic peptides.
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PMID:The natriuretic peptides and their receptors. 144 67

Cultures of renal cells from human or animal origins have allowed the modes of action and the degradation pathways of atrial natriuretic factor (ANF) to be characterized. Human glomerular mesangial and epithelial cells possess ANF receptors of both types, only clearance receptors (C) in mesangial cells, receptors with guanylate cyclase activity (A) and C receptors in epithelial cells which are, in addition, equipped with ectoenzymes rapidly degrading extracellular ANF. Epithelial cells which have been stimulated by ANF secrete cyclic guanosine monophosphate (cGMP) at their apical side. Vascular smooth muscle cells prepared from the rabbit renal cortex also possess A receptors of high affinity and C receptors. Neutral endopeptidase (NEP), an enzyme of which ANF is a specific substrate in the kidney, is expressed at the cell surface. Its expression is inhibited by factors present in the serum and is increased by glucocorticoids. Principal cells of the collecting duct are also a target for ANF via A and C receptors. Taken together, these studies demonstrate that the kidneys are sites both for the physiological effects and the degradation of ANF. Production of cGMP results in vasodilation in the renal cortex, increase of glomerular filtration rate and decrease of sodium reabsorption in the collecting duct. Degradation of ANF occurs via two different ways, its conversion into inactive peptides by NEP and its internalization after binding to C receptors.
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PMID:[Mechanism of action and catabolism of atrial natriuretic factor in cultured human and animal kidney cells]. 146 27


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