Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic-GMP, which plays a pivotal role in visual transduction in the vertebrate retina, is synthesized by guanylate cyclase. The purpose of this study was to localize a rod outer segment-derived particulate guanylate cyclase (ROS-GC) to the retina of several species that have different populations of rods and cones. A rabbit antibody was raised against a synthetic peptide, corresponding to the sequence A107-L125 of bovine ROS-GC. Western blot analysis showed a single immunoreactive band at about 115 kDa with bovine rod outer segments but not with human rod outer segments. Light microscopic immunocytochemistry of tissue sections revealed immunoreactivity in the outer segment layer and in the outer and inner plexiform layers. The rod-rich rat retina showed uniform immunolabeling of outer segments; the cone-containing cat retina showed heavily labeled cone outer segments and lighter labeling of rod outer segments; the cone-rich chicken retina showed a uniformly and intensely labeled outer segment layer. Preincubation of the primary antibody with the peptide completely blocked antibody binding. Electron microscopic immunocytochemistry of the cat retina confirmed the presence of guanylate cyclase in photoreceptor outer segments and demonstrated its association with disk and plasma membranes. These data support a concept in which guanylate cyclase is much more concentrated in the outer segments of cones than rods. The immunolabeling of the plexiform layers suggests that the particulate guanylate cyclase is not unique to the photoreceptor outer segments, and may also play a role in transduction processes of retinal synapses.
J Mol Neurosci 1995
PMID:The bovine rod outer segment guanylate cyclase, ROS-GC, is present in both outer segment and synaptic layers of the retina. 867 3

We report the production of a novel human natriuretic peptide receptor/guanylyl cyclase A (hNPR-A)-selective agonist ANP [G9T, R11S, G16R] (sANP). This agonist has similar affinity to ANP for hNPR-A and 1,000-10,000-fold reduced affinity for the human natriuretic peptide clearance receptor (hNPR-C). sANP was used to directly test the hypothesis that hNPR-A mediates the inhibitory effect of natriuretic peptides on aldosterone generation in a human zona glomerulosa cell line, H295R. Human type A natriuretic peptide and sANP (10(-11) to 10(-6) M) resulted in concentration-dependent increases in cGMP levels and decreases in forskolin (100 nM)- and angiotensin II (5 nM)-induced aldosterone and pregnenolone production. These results revealed an inhibitory effect of both peptides on the agonist-stimulated conversion of cholesterol to pregnenolone (i.e., cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme, EC 1.14.15.6). H295R cells also exhibited angiotensin II- and forskolin-evoked conversion of [3H]cortico-sterone to [3H]aldosterone (i.e., cytochrome P-450 steroid 11 beta-monooxygenase/aldosterone synthase, EC 1.14.15.4). Human type A natriuretic peptide and sANP (10(-7) M) inhibited the angiotensin II-stimulated late pathway but did not affect forskolin-facilitated conversion of corticosterone to aldosterone. Our results directly demonstrate inhibitory effects of hNPR-A-mediated signal transduction on cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme and steroid 11 beta-monooxygenase/aldosterone synthase complex depending on the steroidogenic agonist used.
Mol Pharmacol 1996 Aug
PMID:Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zona glomerulosa cell line. 870 Jan 53

Central areolar choroidal dystrophy (CACD) is a rare inherited retinal disease which causes progressive profound loss of vision in patients during their 4th decade. We have identified a Northern Irish family with 19 affected individuals in three living generations. We have performed a total genome search and established linkage of CACD in this family to chromosome 17p (multipoint Zmax = 5.65 at D17S938). The genes for phosphatidylinositol transfer protein (PITPN), retinal guanylate cyclase (GUC2D), beta-arrestin 2 (ARRB2), pigment epithelium-derived factor (PEDF) and recoverin (RCV1) map to this region and are candidate genes for retinal disease. Analysis of the coding region of the PITPN gene failed to reveal any mutation in this family.
Hum Mol Genet 1996 May
PMID:Localisation of a gene for central areolar choroidal dystrophy to chromosome 17p. 873 41

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 ability of ANP to inhibit the hydrolysis of phosphoinositides was examined in [3H] myoinositol-labeled intact murine Leydig tumor (MA-10) cells. Arginine vasopressin (AVP) stimulated the formation of inositol monophosphate (IP1), inositol bisphosphate (IP2), and inositol trisphosphate (IP3) both in a time-and dose-dependent manner in MA-10 cells. ANP inhibited the AVP-induced formation of IP1, IP2, and IP3 in these cells. The inhibitory effect of ANP on the AVP-stimulated formation of IP1, IP2, and IP3 accounted for 30%, 38% and 42%, respectively, which was observed at the varying concentrations of AVP. ANP caused a dose-dependent attenuation in AVP-stimulated production of IP1, IP2 and IP3 with maximum inhibition at 100 nM concentration of ANP. The production of inositol phosphates was inhibited in the presence of 8-bromo cGMP in a dose-dependent manner, whereas dibutyryl-cAMP had no effect on the generation of these metabolites. The LY 83583, an inhibitor of guanylyl cyclase and cGMP production, abolished the inhibitory effect of ANP on the AVP-stimulated production of inositol phosphates. Furthermore, 10 microM LY 83583 also inhibited the ANP-stimulated guanylyl cyclase activity and the intracellular accumulation of cGMP by more than 65-70%. The inhibition of cGMP-dependent protein kinase by H-8, significantly restored the levels of AVP-stimulated inositol phosphates in the presence of either ANP or exogenous 8-bromo cGMP. The results of this study suggest that ANP exerts an inhibitory effect on the production of inositol phosphates in murine Leydig tumor (MA-10) cells by mechanisms involving cGMP and cGMP-dependent protein kinase.
Mol Cell Biochem 1996 May 24
PMID:Atrial natriuretic peptide inhibits the phosphoinositide hydrolysis in murine Leydig tumor cells. 881 70

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

There have been conflicting reports about the occurrence and/or activity of atrial natriuretic peptide (ANP) sensitive guanylyl cyclase in the immune system. This study reports on ANP-sensitive guanylyl cyclase mRNA expression and guanylyl cyclase activity in human peripheral blood mononuclear cells (PBMC). Reverse transcription polymerase chain reaction (RT-PCR) shows that activated human PBMC of healthy blood donors express functional active ANP-sensitive guanylyl cyclase after vitro culture, whereas freshly isolated PBMC show neither specific mRNA for particulate guanylyl cyclase nor ANP-sensitive activity of this enzyme. To define the subpopulation of PBMC expressing this enzyme, cultivated PBMC were subfractioned and analyzed by RT-PCR and in situ PCR. Only CD3+ PBMC showed mRNA for ANP-sensitive guanylyl cyclase. Induction of the guanylyl cyclase required coincubation with other cells, indicating that a factor or factors secreted from cells other than CD3+ cells induces this expression. In summary, ANP-sensitive guanylyl cyclase is an inducible enzyme in human CD3+ PBMC in contrast to other cells where it is considered to be constitutive.
J Mol Med (Berl) 1996 Oct
PMID:Particulate ANP-sensitive guanylyl cyclase: induction in cultured human peripheral CD3+ mononuclear blood cells. 891 84


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