Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory effect of atrial natriuretic peptide (ANP) on angiotensin II (AII)-stimulated aldosterone secretion has been previously studied in rat and bovine adrenal zona glomerulosa cells in primary culture. However the understanding of the mode of action of ANP at the molecular level has been hampered by limitations of those primary cell culture systems and by the lack of cell lines from human adrenal cortex. Here we demonstrate the presence of fully functional ANP receptors in the recently characterized AII-responsive adrenocortical carcinoma cell line H295R. Specific saturable binding of 125I-rANP to H295R cell membrane preparations revealed a single class of high affinity binding sites with a density of 20 fmol/mg of protein. The pharmacological profile of this ANP receptor was documented by competitive binding of 125I-rANP with naturally occurring natriuretic peptides. rANP was the most potent with a Kd of 42 pM. pBNP32 was less potent with a Kd of 174 pM. 125I-rANP binding was not competed by pCNP (NPRB-specific ligand) nor by C-ANF (NPRC-specific ligand). Photoaffinity labeling of membrane preparations with 125I-BPA-ANP revealed a single specific protein of molecular weight around 130 kDa. This protein was further identified by immunodetection with a specific antibody directed to the human ANP-specific receptor NPRA. Natriuretic peptides stimulated cGMP production by the receptor-coupled guanylate cyclase with the same specificity. Aldosterone production by AII-stimulated H295R cells was dose-dependently inhibited by rANP with an ED50 of 1.5 nM. In addition, we used this model to test two chimeric analogs of ANP and BNP. pBNP1 and pBNP3 were, respectively, 4- and 2-fold more potent than rANP in competing for 125I-rANP binding with Kd of 10 and 20 pM. pBNP1 was 24-fold more potent in inhibiting AII-stimulated aldosterone production with ED50 of 63 pM. pBNP1 is therefore the most potent natriuretic peptide analog tested. In summary, the human H295R cell line contains NPRA receptors positively coupled to the particulate guanylate cyclase and that antagonize angiotensin II stimulation of aldosterone secretion.
Mol Cell Endocrinol 1996 Apr 19
PMID:The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. 873 99

The type C natriuretic peptide (CNP)-activated guanylate cyclase (CNP-RGC) is a single-chain transmembrane-spanning protein, containing both CNP binding and catalytic cyclase activities. Upon binding CNP to the extracellular receptor domain, the cytosolic catalytic domain of CNP-RGC is activated, generating the second messenger cyclic GMP. Obligatory in this activation process is an intervening signal transduction step which is regulated by ATP binding to the cyclase. This bridges the events of ligand binding and cyclase activation. A defined sequence motif (Gly499-Xa-Xa-Xa-Gly503), termed ATP regulatory module (ARM), is critical for this step. The present study shows that ATP not only amplifies the signal transduction step, it also concomitantly reduces the ligand binding activity of CNP-RGC. Reduction in the ligand binding activity is a consequence of the transformation of the high affinity receptor-form to the low affinity receptor-form. A single ARM residue Gly499 is critical in the mediation of both ATP effects, signal transduction and ligand binding activity of the receptor. Thus, this residue represents an ATP bimodal switch to turn the CNP signal on and off.
Mol Cell Biochem 1995 Nov 22
PMID:ATP modulation of the ligand binding and signal transduction activities of the type C natriuretic peptide receptor guanylate cyclase. 875 Nov 65

Oxidative stress mediated by hydrogen peroxide (H2O2) increases coronary flow (CF) in Langendorff-perfused rat hearts. We investigated the possible role of nitric oxide (NO) in H2O2-induced vasodilation. A dose-response study was conducted to find a concentration of H2O2 which increased CF without influencing left ventricular developed (LVDP) or end-diastolic (LVEDP) pressures. 80(n = 10), 100 (n = 7), 120 (n = 7), 140 (n = 7), 160 (n = 7), and 180 (n = 10) microM H2O2 was infused for 10 min, followed by recovery for 50 min. 80 microM H2O2 increased CF to a maximum of 143 +/- 4 (mean +/- S.E.M) percent of initial value after 15 min observation (p < 0.001 compared to buffer only), with no effect on LVDP or LVEDP. Another series of hearts were perfused with N-nitro-L-Arginine methylester (L-NAME, 1 mM), methylene blue (MB, 50 microM), or haemoglobin (Hb, 10 microM), without (n = 7 in each) or with (n = 10 in each) 80 microM H2O2 for 10 min. L-NAME, MB, and Hb alone increased CF, but attenuated the H2O2-induced increase of CF.LVDP was depressed when L-NAME, MB or Hb were given in conjunction with 80 microM H2O2. In summary, H2O2 concentration-dependently increased LVEDP and depressed LVDP. The H2O2-induced increase of CF was independent of concentration. Inhibition of NO synthesis, action, or soluble guanylate cyclase attenuated the H2O2-induced increase of CF, and depressed LVDP when given together with H2O2. H2O2 induces a NO-dependent vasodilation, and inhibition of NO is detrimental to left ventricular function after H2O2-mediated oxidative stress.
Mol Cell Biochem 1996 Jun 07
PMID:The role of nitric oxide in the cardiac effects of hydrogen peroxide. 881 4

The study is concerned with the mechanism of activation of soluble guanylate cycla-se by guanidine thiol derivatives-a new class of enzyme activators. Guanidine thiols contain both the guanidine and SH group which act, respectively, as donor and acceptor of nitric oxide (NO). The role of guanidine thiol SH group in the mechanism of soluble guanylate cyclase activation was studied. Three guanidine thiol derivatives were tested: mercaptoethylguanidine, its disulfide and S-methyl mercaptoethylguani-dine. All three compounds proved to be NO-synthase substrates and, simultaneously, guanylate cyclase activators. The degrees of guanylate cyclase activation by mercaptoethylguanidine and its disulfide were, respectively, two and four times higher than that by L-arginine. The stimulatory effects of S-methyl mercaptoethylguanidine and L-arginine were evaluated and found to be of the same order. The important role of S-acceptor group of guanidine thiols in the mechanism of guanylate cyclase activation increase provides an explanation for different intensities of guanylate cyclase activation by the compounds tested. NO-acceptor properties of guanidine thiols disulfide bonds in the synthase mechanism of NO generation were first reported.
Biochem Mol Biol Int 1996 Mar
PMID:Mechanism of activation of soluble guanylate cyclase by guanidine thiols--a new class of enzyme activators. 882 10

Patients with systemic hypertension of various etiologies maintain their pulmonary artery pressures within normal limits. We have reported in isolated perfused rat lungs that low basal tone appears to be regulated by nitric oxide (NO)-dependent and -independent mechanisms of soluble guanylate cyclase activation, and similar results are seen in isolated small pulmonary arteries (PA) from these animals. The abdominal aorta of rats was ligated above the left and below the right renal artery (aortic coarctation, AC). The mean arterial pressure (MAP) and pulmonary artery pressure (PAP) of 24-h post-AC rats (MAP 123 +/- 7.1 mm Hg and PAP 4.2 +/- 0.9 mm Hg) showed no significant change when compared with those of sham control rats (MAP 116 +/- 7.0 mm Hg and PAP 5.0 +/- 0.04 mm Hg). Hypoxic contractions in isolated small rat PA (160 to 260 microns diameter) were significantly increased from 56.7 +/- 12.0 mg in the control group to 139 +/- 31 mg in the 24-h post-AC rats (P < 0.05). PA contractions in the presence of 100 microM nitro-L-arginine (NLA) increased from 102 +/- 34 mg among the sham control group to 261 +/- 30 mg among the 24-h post AC rats (P < 0.05). After NLA, the hypoxic contractions decreased to 15 +/- 2.9 mg in the control rats and 45 +/- 16 mg in the 24-h post-AC rats when compared with pre-NLA values (P < 0.05). Western and Northern blotting of protein and messenger ribonucleic acid (mRNA) extracted from the whole rat lung showed a significant rise in endothelial cell nitric oxide synthase (EcNOS; 207 +/- 34%) and EcNOS mRNA (2-fold) when comparing controls with 24-h post-AC rats. These data indicate that there is increased EcNOS activity and synthesis that maintain low PA tone in these rat models as early as 24 h after AC; in addition, this effect is independent of the systemic blood pressure.
Am J Respir Cell Mol Biol 1996 Oct
PMID:Early regulatory changes in rat pulmonary artery of renin-dependent systemic hypertension models. 887 80

Since nitric oxide (NO) has been widely accepted as a novel neuromodulator, which activates soluble forms of guanylate cyclase to increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, the effect of water-soluble substance in cigarette smoke on cyclic GMP levels were investigated using nerve terminals prepared from rat cerebral cortex. Although the smoke-substance itself failed to affect cyclic GMP levels in the synaptosomes, the smoke-substance significantly inhibited the increases in cyclic GMP levels induced by NO donors. The blocking effect of the smoke-substance was inhibited by concomitant incubation with superoxide dismutase, but not with mannitol. In addition, the effect of smoke-substance was mimicked by products of the xanthine/xanthine oxidase system, but not by nicotine. The effect of smoke-substance was preserved at least 7 days after they were stored at room temperature. Therefore, these results suggest that the smoke-substance may possess long half-lives to produce the radicals which inactivate NO, and to inhibit the increase in cyclic GMP levels in nerve terminals. The interference with NO may explain the part of mechanism in effects of cigarette smoke on neuronal functions.
Brain Res Mol Brain Res 1996 Nov
PMID:Effects of cigarette smoke on nitric oxide-induced increase in cyclic GMP in nerve terminals of rat cerebral cortex. 891 78

C-type natriuretic peptide (CNP), a hormone which stimulates particulate guanylate cyclase activity, was studied for its ability to stimulate chloride permeability through the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells. Two cell lines, Calu-3 and CF-T43, were used as models of normal and cystic fibrosis (CF) airway epithelial cells, respectively. Calu-3 cells, derived from a lung carcinoma, express relatively high levels of wild-type CFTR. CF-T43 is a transformed line derived from a nasal polyp and expresses the mutant CFTR, deltaF508. Calu-3 cells exposed to the nucleotide guanosine-3',5'-monophosphate (cGMP) analogue 8-Br-cGMP exhibit increased 36Cl- efflux, demonstrating that cGMP can mediate changes in chloride permeability. CNP induces a bumetanide-sensitive short circuit current across Calu-3 monolayers. Whole-cell currents stimulated by CNP display linear current-voltage relationships and have inhibitor pharmacology and ion selectivity consistent with CFTR channel activity. Sodium nitroprusside (SNP), an activator of soluble guanylate cyclase, and CNP both increase cGMP levels and short circuit current in Calu-3 cells. In contrast, exposure of CF-T43 cells to CNP resulted in an increased 36Cl- efflux rate only when combined with the adenylate cyclase agonist isoproterenol and the response was sensitive to kinase inhibitors. CF-T43 cells exposed to isoproterenol and SNP showed no increase in chloride efflux. Together, these data indicate that CNP can activate wild-type and mutant CFTR through a cAMP-dependent protein kinase pathway and that the sensitivity of Calu-3 cells for this stimulation is greater than that of the CF-T43 cells.
Am J Respir Cell Mol Biol 1997 Apr
PMID:C-type natriuretic peptide increases chloride permeability in normal and cystic fibrosis airway cells. 911 58

The envelope protein (gp52) of the mouse mammary tumor virus (MMTV) can stimulate RNA synthesis via binding to its cellular receptor on mammary epithelium. This effect was mimicked by either nitric oxide (NO) or 8-bromo-cGMP and was blocked by an NO inhibitor. Furthermore, the effects of gp52 and 8-bromo-cGMP were not additive at maximal concentrations, suggesting that they were using the same signaling route. Finally, gp52 elevated cGMP levels in mammary epithelium. These data suggest that gp52 activates the following transduction pathway in this tissue: gp52-->NO synthase-->NO-->soluble guanylate cyclase cGMP RNA synthesis. In contrast to the mammary gland, gp52 inhibited RNA synthesis in the diaphragm. However, the effect was again mimicked by NO, blocked by an NO inhibitor, and the effects of gp52 and NO were not additive. Therefore, it appears that gp52 is using the NO-cGMP pathway in both tissues, but that muscle tissue may be more susceptible to the toxic effects of NO.
Mol Cell Endocrinol 1997 Apr 25
PMID:Second messengers induced by the envelope protein of a retrovirus. 917 26

The possible role of altered humoral immune response in the pathogenesis of the chronic chagasic cardioneuromyopathy was examined by analyzing the interaction of IgG from T. cruzi infected patients with cardiac muscarinic acetylcholine receptors (mAChR). Human chagasic IgG by activating cardiac M2 mAChR, simulated the agonist actions triggering negative inotropic effect, inositol phosphate accumulation, nitric oxide synthase stimulation and increased production of cyclic GMP. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase activities; prevented chagasic IgG effects on signaling pathways involved in M2 mAChR activation. In addition, sodium nitroprusside or 8-bromo cyclic GMP, mimicked the chagasic IgG effect associated with cholinergic-mediated cellular transmembrane signals. Moreover, these chagasic IgG immunoprecipitated the mAChRs solubilized from cardiac membranes. By means of SDS-PAGE and immunoblotting analysis, chagasic sera recognized a band of 70-75 kDa. The major protein recognized by chagasic IgG had an Rf coincident with the peak of [3H] propylbenzilylcholine mustard with an apparent molecular weight similar to that of mAChRs, which disappeared in the presence of atropine. The specificity of this interaction was checked by immunoprecipitation of rat cardiac mAChR and immunoblotting of pure human M2 mAChRs. Chronic interaction of chagasic IgG with myocardial mAChRs, behaving as a muscarinic agonist, might lead to cell dysfunction or tissue damage. Also, these antibodies could produce desensitization, internalization or degradation of mAChRs; explaining the progressive blockade of mAChRs in myocardium with parasympathetic denervation, a phenomenon that has been described in the course of Chagas' cardioneuromyopathy.
J Mol Cell Cardiol 1997 Jul
PMID:Participation of nitric oxide signaling system in the cardiac muscarinic cholinergic effect of human chagasic IgG. 923 39

Relatively high concentrations of azathioprine had an inhibitory effect on interleukin 8 (IL-8)- or formyl-methionyl-leucyl-phenylalanine-activated (fMLP)-chemotaxis by human neutrophils. However, application of low concentrations of azathioprine in a concentration gradient gave a chemotactic stimulation to random migration. Stimulation of migration was maximal at a concentration of 5 microM azathioprine; at higher concentrations stimulation decreased again. The activating effect of azathioprine is located in the mercaptopurine moiety of the molecule, since mercaptopurine also stimulated neutrophil migration. In contrast to some other chemotactic agents such as fMLP and IL-8, an activating concentration (5 microM) of azathioprine did not cause an upregulation of CD11b expression on neutrophils in suspension. High concentrations of azathioprine (1 mM) inhibited CD11b expression of fMLP- or IL-8- activated neutrophils; the latter could explain the inhibitory effect of azathioprine. Azathioprine caused a transient stimulation of cGMP level; inhibitors of guanylate cyclase inhibited azathioprine-stimulated migration, suggesting that cGMP was associated with the stimulating effect of azathioprine on migration. Antagonists of cGMP-dependent protein kinase (G-kinase) strongly inhibited azathioprine-activated migration, indicating that the effect of azathioprine proceeds via G-kinase. The antagonists had only a marginal effect on inhibition of IL-8-activated chemotaxis by high concentrations of azathioprine, thus the G-kinase seems not to be of great importance on the inhibitory effect of azathioprine.
Cell Mol Life Sci 1997 Jul
PMID:A cyclic GMP- and G-kinase-dependent effect of azathioprine on migration by human neutrophils. 928 61


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