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)

Although atrial and brain natriuretic peptides are well known to be involved in the regulation of cardiovascular and endocrine functions as circulating hormones, the roles of the C-type natriuretic peptide (CNP) remain unknown. We examined the effects of CNP on the secretion of aldosterone and cyclic nucleotides from bovine adrenal zona glomerulosa cells in culture. CNP produced a dose-dependent increase in the basal secretion of cGMP, with an EC50 of 3.8 x 10(-10)M. CNP significantly inhibited the ACTH-induced increase in aldosterone and cAMP in a dose-related manner, with an IC50 of 3.6 x 10(-10)M. Although ACTH itself did not increase cGMP secretion, the addition of CNP elicited a significant increase in cGMP secretion. The effects of CNP on the basal secretion of cGMP and the ACTH-induced secretion of aldosterone were significantly reversed by a nonpeptide natriuretic peptide receptor antagonist, HS-142-1. CNP immunoreactivity was localized in the zona glomerulosa by immunohistochemical staining. In addition, expression of CNP messenger RNA and natriuretic peptide B receptor messenger RNA was demonstrated by RT-PCR in the zona glomerulosa tissue and cells in culture. These findings suggest that CNP is a local factor regulating ACTH-induced aldosterone secretion through a guanylyl cyclase-cGMP pathway.
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PMID:C-type natriuretic peptide as a possible local modulator of aldosterone secretion in bovine adrenal zona glomerulosa. 853 40

The cellular distribution of guanylyl cyclase coupled natriuretic peptide receptors type A (GC-A) and type B (GC-B) was examined by immunocytochemistry in normal rat kidney, and compared with the distribution of the vacuolar H(+)-ATPase. Staining for GC-A was found in glomeruli, thin limbs of Henle's loop, cortical collecting tubule, and inner medullary collecting duct. Staining for GC-B was found in glomeruli and the same nephron sections as GC-A, with the exception of the thin limbs. In the cortical collecting tubule, GC-A was found in both principal and intercalated cells; GC-B was restricted to the apical pole of alpha intercalated cells. In inner medullary collecting duct cells, GC-A was located on the basal membrane, whereas GC-B was found in the apical pole. The different pattern of polarization of natriuretic peptide receptors in the inner medulla provides a plausible basis for the different physiologic effects of atrial natriuretic factor and C-type natriuretic peptide. The results also suggest the possibility that GC-B is involved in the regulation of bicarbonate transport in the cortical collecting tubule.
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PMID:Natriuretic peptide receptors A and B have different cellular distributions in rat kidney. 858 68

The polarized expression of guanylyl cyclase-coupled natriuretic peptide receptors, types A (GC-A) and B (GC-B), was measured in inner medullary collecting ducts (IMCD) of normal and ischemic rat kidneys, as well as in IMCD cells. Exposure of normal rat kidney medulla to an anti-GC-A antibody demonstrated a propensity of receptor staining on the cellular basal membrane. The polarization of GC-A receptors was lost in the ischemic kidney. The maximal binding capacity of 125I-atrial natriuretic factor (ANF) to the basal membrane of the inner medullary cell line mIMCD-K2 was five times greater than that to the apical membrane. ANF or C-type natriuretic peptide (CNP) added to the basal side of cultured cells resulted in guanosine 3',5'-cyclic monophosphate formation that was greater than when applied to the apical side. Depletion of ATP stores in cultured cells was followed by an increase of 125I-ANF binding to apical cellular membranes. Similar results were obtained when receptor guanylyl cyclase activity was assayed. In conclusion, these results suggest that functional GC-A and GC-B receptors are present predominantly on the basal membrane of IMCD. However, depletion of cellular ATP stores such as in ischemia is followed by a partial loss of polarization.
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PMID:Polarized distribution of renal natriuretic peptide receptors in normal physiology and ischemia. 859 88

We determined previously that astroglia cultured from newborn rat brain contain both guanylyl cyclase-coupled and atrial natriuretic peptide (ANP)-C natriuretic peptide receptors. Here, we investigated the effects of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) on these receptor subtypes in cultured astroglia to understand the intracellular processes involved in the modulation of natriuretic peptide receptors in these cells. PMA (10 nM to 1 microM; 15 min to 24 h) treatment elicited a time- and concentration-dependent decrease in the numbers of 125I-labeled ANP specific binding sites, which was inhibited by the PKC antagonist staurosporine (500 nM). Furthermore, PMA (100 nM, 2 or 24 h) treatment elicited a significant decrease in the specific binding of 125I-des-Cys-Cys-ANP, an ANP-C receptor selective ligand. PMA (10 nM to 1 microM; 30 min) treatment also significantly decreased ANP (100 nM)-stimulated guanosine 3', 5'-cyclic monophosphate levels in cultured astroglia, an effect unmodified by phosphodiesterase inhibition. These data indicate that PKC modulates both guanylyl cyclase-coupled and ANP-C natriuretic peptide receptors in cultured astroglia.
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PMID:Protein kinase C modulates natriuretic peptide receptors in astroglial cultures from rat brain. 863 52

Adipose tissue of the mesenteric territory contains large quantities of natriuretic peptide receptors (NPR) mainly of the NPR-C subtype. Guanylyl cyclase-bound receptors are also present since atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are equally potent in activating this enzyme. While searching for a potential biological role for NP in adipocytes we observed that ANP-mediated generation of cyclic GMP (cGMP) was potentiated when the cells were simultaneously treated with isoproterenol. Indeed, isoproterenol, a beta-adrenergic agonist, and forskolin, an activator of adenylyl cyclase, can both double or triple cGMP production in response to ANF stimulation. There was a direct correlation between the level of cyclic AMP (cAMP) generated and the level of NP-mediated cGMP production suggesting that a cAMP-dependent mechanism may be responsible of this potentiation. To determine whether or not this phenomenon was unique to adipocytes, NPR subtypes were characterized in 4 established cell lines and their cAMP-dependent cGMP behavior examined. A10 and A7r5 smooth muscle cells showed identical ratio of NPR subtypes with about 95% NPR-C and 5% NPR-B. PC12 cells presented 100% NPR-A and NIH 3T3 fibroblasts 50% NPR-C and 50% NPR-B. Regardless of the NPR subtype, forskolin could not potentiate the cGMP generation in these cell lines. These data indicate that the cAMP-dependent potentiation of the NP-mediated cGMP production is unique to adipocytes, appears independent of the guanylyl cyclase-linked NPR subtypes and may be involved in the sensitization of the guanylyl cyclase domain of NPR for a potential biological role of NP in the adipose tissue.
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PMID:Specific potentiation by cyclic AMP of natriuretic peptide-mediated cyclic GMP production in adipose tissue. 864 24

C-type natriuretic peptide (CNP) is a local regulator in the brain and vascular wall. We present data to demonstrate the production and action of CNP in the osteoblast. CNP increased cGMP production, far more potently than atrial natriuretic peptide (ANP) in an osteoblastic cell line, MC3T3-E1. Since ANP and CNP are the ligands for two particulate guanylate cyclases, guanylate cyclase-A (GC-A) and guanylate cyclase-B (GC-B), respectively, these results reveal the expression of GC-B in MC3T3-E1. In addition, CNP mRNA and CNP-like immunoreactivity were detected in cell extracts from MC3T3-E1 and its culture medium, respectively. Both CNP and 8-bromo cGMP dose-dependently decreased [3H]thymidine uptake, without affecting alkaline phosphatase activity. These results indicate that CNP is a novel autocrine/paracrine regulator of osteoblast and suggest the presence of "bone natriuretic peptide system."
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PMID:C-type natriuretic peptide as an autocrine/paracrine regulator of osteoblast. Evidence for possible presence of bone natriuretic peptide system. 866 Mar 52

1. While the natriuretic peptides (atrial, brain and C-type) mediate potent endothelium-independent vasorelaxing actions in vitro, the role of the endogenous natriuretic peptide system in vascular regulation in vivo remains unclear. 2. HS-142-1 is a novel natriuretic peptide receptor antagonist derived from a fungus named Aureobasidium sp. which selectively blocks particulate guanylate cyclase-linked natriuretic peptide A and B receptors that bind atrial, brain and C-type natriuretic peptide, and thus attenuates the generation of cGMP. 3. To characterize the vascular actions of the endogenous natriuretic peptide system in the control of basal coronary and systemic haemodynamics, six normal male mongrel anaesthetized dogs were studied while a second group of five dogs served as a control. HS-142-1 was given as an intravenous bolus at 3 mg/kg and was studied over five 20 min periods. 4. No significant difference after HS-142-1 was observed in mean arterial pressure, heart rate, cardiac output, right atrial pressure, pulmonary capillary wedge pressure or systemic vascular resistance compared with control. In contrast, a significant increase in coronary vascular resistance and decrease in coronary blood flow were observed which were different from the baseline values and the responses of the control group. 5. These studies demonstrate that HS-142-1 produces vasoconstriction in the coronary circulation. We conclude that the endogenous natriuretic peptide system, which is of cardiac and endothelial cell origin, is an important regulator of basal coronary vascular tone.
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PMID:Role for the endogenous natriuretic peptide system in the control of basal coronary vascular tone in dogs. 866 72

The effects of natriuretic peptides on cGMP formation and [125I]ANP binding in human trabecular meshwork cells were investigated. CNP at 1 microM stimulated cGMP formation approximately 18-25 fold, with a half maximal effective concentration approximately 20-30nM. BNP at 1 microM stimulated approximately 7 fold, while ANP stimulated cGMP formation 2-fold at 1 microM but had little or no effect at concentrations below 1 microM. Displacement binding of [125I]ANP to intact TM cells in the presence of unlabeled ANP indicated a single binding site with a dissociation constant approximately 0.15nM.c-ANP, which binds specifically to natriuretic peptide C receptors, displaced > 95% [125I]ANP binding to surface receptor sites with a half-maximal effective concentration comparable to that of ANP or BNP. c-ANP had no inhibitory effect on CNP stimulation of cGMP formation. The data suggest that human TM cells possess natriuretic peptide B receptors as the primary guanylyl cyclase-containing subtype and C receptors as the numerically predominant subtype of natriuretic peptide receptors.
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PMID:Natriuretic peptide receptors on human trabecular meshwork cells. 867 Jul 21

Isatin is an endogenous indole with a distinctive distribution in brain and tissues. In the brain, the highest levels have been found in the hippocampus (0.1 microgram/g), and an immunocytochemical stain has shown specific localization within particular cells. In vitro, its most potent known actions are as an inhibitor of monoamine oxidase B (IC50 approximately 3 microM), and of atrial natriuretic peptide (ANP) receptor binding and ANP-induced guanylate cyclase (both with an IC50 approximately 0.4 microM). In vivo, isatin administration (10-200 mg/kg) causes an increase of monoamine neurotransmitter levels in the brain. Isatin is anxiogenic in animal models at doses of 10-20 mg/kg and sedative at higher doses. Its anxiogenic effects are unlikely to be due to inhibition of monoamine oxidase, but may possibly stem from interaction with the ANP system. Isatin may mediate a link between monoamines and the natriuretic peptide system, and its analogues may provide new pharmacological tools.
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PMID:Isatin: a link between natriuretic peptides and monoamines? 868 91

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.
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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


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