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)

Adenylate cyclase and cyclic AMP phosphodiesterase activities in the thyroid gland were significantly reduced after hypophysectomy, followed by a gradual restoration of the enzyme activities to the levels seen in sham-operated rats whereas a slight and persistent reduction was evident in guanylate cyclase and cyclic GMP phosphodiesterase activities in the same tissue. These changes in enzyme activities were restored by TSH administration but not by ACTH. The recovery of activity produced by TSH administration was inhibited by cycloheximide. Hypophysectomy, or TSH and cycloheximide administration, did not produce any significant changes in the concentrations of calmodulin, suggesting that the alteration of these enzyme activities is not induced by a decrease in the concentration of calmodulin. Since forskolin activation of adenylate cyclase did not restore the reduced activity in the hypophysectomized rat thyroid to the level found in the sham-operated control rat thyroid, we conclude that there is a reduction of the amount of enzyme after hypophysectomy rather than a change of the active site on adenylate cyclase. The spontaneous restoration of adenylate cyclase and cyclic AMP phosphodiesterase activities after hypophysectomy implies that cyclic AMP-metabolizing enzymes are responsive to an autoregulatory mechanism in thyroid follicular cells.
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PMID:Effect of hypophysectomy on cyclic 3',5'-nucleotidemetabolizing enzymes in the rat thyroid gland. 286 Jan 96

While atrial natriuretic factor (ANF) does not influence ACTH secretion, it was reported to have a marked stimulatory effect on the intracellular accumulation of cGMP in rat anterior pituitary cells in culture. Since many biological actions of ANF appear coupled to its excitatory action on target cell guanylate cyclase, the current study was designed to characterize the ANF-induced cGMP response in anterior pituitary with a view to determining whether the nucleotide plays a regulatory role in the secretory function of this gland. A 3 min exposure of cells in primary culture to 300 nM ANF (99-126) or 100 microM sodium nitroprusside (SNP), a stimulator of guanylate cyclase, causes maximal 10- and 3-fold elevations of cGMP levels, respectively. Following a progressive decrease, 6- and 2-fold increases over basal cGMP levels are still observed after 180 min of incubation with ANF (99-126) and SNP, respectively. The half-maximal stimulation of cGMP accumulation induced by a 10 min exposure to ANF (99-126), or rat atriopeptin II (ANF 103-125) is observed at 9 +/- 2 and 125 +/- 22 nM, respectively. ANF fragments (99-109) and (111-126), as well as human cardiodilatin (hANF 1-16), do not alter cGMP levels. Basal and ANF-induced cGMP levels are at least 10-fold higher in cell populations enriched in gonadotrophs compared to gonadotroph-impoverished preparations. A 3 h incubation of cells with ANF (0.1-1000 nM), however, fails to modify spontaneous or LHRH-induced LH secretion. Similarly, ANF does not alter spontaneous release of GH, TSH or PRL. The data suggest indirectly that gonadotrophs represent a principal site at which ANF acts to stimulate cGMP synthesis, but that the nucleotide is not a specific regulator of the LH secretory process; nor is it generally involved as a second messenger in the secretory function of any cell type of the anterior pituitary gland.
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PMID:Atrial natriuretic factor-induced cGMP accumulation in rat anterior pituitary cells in culture is not coupled to hormonal secretion. 302 38

In order to investigate the presence of alpha-adrenergic receptors in human thyroid, we have studied the effect of alpha-adrenergic agonists and antagonists on cGMP cellular content of human thyroid cells in primary culture. Epinephrine as well as TSH were not able to modify the cGMP cellular levels, while norepinephrine significantly increased cGMP accumulation already at 10 nM, a dose inactive on cAMP accumulation. A non selective alpha-adrenergic antagonist, phentolamine, significantly inhibited cGMP accumulation induced by norepinephrine. Norepinephrine-induced cGMP accumulation was unaffected by prazosin, an alpha 1-adrenergic antagonist, but was abolished by yohimbine, an alpha 2-adrenergic antagonist. Phenylephrine, an alpha-adrenergic agonist, produced an increase of cellular cGMP levels without modifying cAMP content. In the presence of TSH, the cGMP response to norepinephrine was not modified; however, the increase of cAMP levels was inhibited by norepinephrine at doses inactive on cAMP accumulation, but active on cGMP levels. The present results demonstrate the existence in human thyroid cells of alpha 2-adrenergic receptors, regulating the guanylate cyclase system. It may be postulated that the counter-regulation exerted by alpha-adrenergic agonists on the response to TSH operates on the TSH-dependent adenylate cyclase.
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PMID:Evidence for alpha-adrenergic receptors acting through the guanylate cyclase system in human cultured thyroid cells. 613 25

Forskolin, at 10(-11) M, stimulates guanylate cyclase activity in primary human thyroid cell cultures, but does not modify cAMP accumulation. At a 10-fold higher concentration it still stimulates guanylate cyclase activity and becomes an inhibitor of cAMP production. Above 10(-9) M, forskolin stimulation of cGMP decreases, while it also becomes a stimulator of cAMP production. There is an additive effect of TSH and forskolin on cAMP production at concentrations of the diterpene which are stimulatory. Concentrations of forskolin which are inhibitory for cAMP, but stimulatory for cGMP, are inhibitory for TSH stimulation of cAMP. The addition of 8-bromo-cGMP duplicates the forskolin effect at low concentrations.
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PMID:Forskolin perturbs cGMP as well as cAMP levels in human thyroid cells. 620 36

Thyrotropin (TSH) regulation of atrial natriuretic factor (ANF) receptors was studied in the rat thyroid follicular cell line, FRTL-5. Exposure of FRTL-5 cells to 1 mU/ml TSH for 7 days resulted in a tenfold increase in ANF receptors (Bmax = 188 fmol/mg protein) compared with control (Bmax = 18 fmol/mg protein), without affecting binding affinity. An identical treatment of porcine thyrocytes with TSH resulted in a 50% decrease in ANF binding sites. Displacement binding studies indicated that > 80% of the ANF receptors in FRTL-5 cells belong to the ANF-R1 (guanylate cyclase-coupled) receptor subtype. By contrast, > 98% of the ANF receptors in porcine thyrocytes were of the ANF-R2, or clearance, receptor subtype. Intracellular cGMP content was increased thirty-sixfold in FRTL-5 cells by 1 microM ANF, but only 2.5-fold in porcine thyrocytes. cAMP levels were unaffected by ANF in either cell type. Northern blot analysis of poly A mRNA extracted from FRTL-5 cells incubated 2 days in the presence of 100 nM ANF indicated a twofold increase in thyroglobulin mRNA content compared with control. These findings suggest that the ANF-R1 receptor, preferentially expressed in FRTL-5 cells and regulated by TSH, might play a role in regulating thyroid hormone production.
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PMID:Atrial natriuretic factor (ANF) binds to thyrotropin-regulated receptors in FRTL-5 cells and increases thyroglobulin mRNA. 793 23

Sodium nitroprusside spontaneously breaks down in solution to produce the vasodilator nitric oxide. In many cell types, this stimulates the cytosolic form of the enzyme guanylate cyclase, resulting in the elevation of cyclic GMP (cGMP). We have investigated the effect of sodium nitroprusside on the generation of cGMP in primary human thyrocytes and the SV40-transfected human thyroid cell line SGHTL-189. A dose-dependent increase in cGMP was obtained and the maximum response was observed with concentrations above 10 microM sodium nitroprusside in both cell types. Methylene blue (50 microM) had no significant effect on basal cGMP production but inhibited the effect of sodium nitroprusside at all concentrations tested, thus demonstrating that the effect was due to nitric oxide. Sodium nitroprusside had no effect on cyclic AMP (cAMP) production in these cells. TSH at 100 and 1000 microU/ml significantly stimulated the production of cAMP, but not that of cGMP, in primary human thyrocytes. Sodium nitroprusside had no significant effect on basal or TSH-stimulated triiodothyronine secretion in primary human thyrocytes. Forskolin (10 microM) significantly stimulated cAMP production in both primary thyrocytes and SGHTL-189 cells. Although forskolin had no significant effect on basal cGMP production, sodium nitroprusside-stimulated cGMP production was significantly reduced by forskolin. However, this inhibitory effect was not related to the production of cAMP.
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PMID:Nitric oxide stimulates cyclic GMP in human thyrocytes. 809 15

Methylene blue (MB) is a thiazine dye used in the treatment of methemoglobinemia. It may represent a new class of anti-oxidant drugs which competitively inhibit the reduction of molecular oxygen to superoxide by acting as an alternative electron acceptor for tissue oxidases. Because of its strong free radicals scavenging effect MB was experimentally used in the treatment of reperfusion syndrome. MB is soluble guanylate cyclase inhibitor. It was found to inhibit the stimulation of soluble guanylate cyclase by nitric oxide and vasodilatators. Another effect of MB is inhibition of prostacyclin synthesis by endothelial cells and isolated arteries independently of its effects on cGMP accumulation. We investigated the MB in series of experimental endocrine situations in which its free radicals scavenging effect could play a role. We observed that MB partly inhibited the increase in adenohypophyseal weight, cAMP and blood prolactin levels in male rats after the administration of estrogens. MB also blocked the increase of another free radicals scavenger-the metalloenzyme ceruloplasmin in the blood of estrogenized rats and prevented the increase of bone mineral after estradiol treatment. MB produced a decrease in adenohypophyseal ascorbic acid content. The blood thyroxine levels increased and the anterior pituitary TSH concentration decreased after MB treatment.
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PMID:Methylene blue--an endocrine modulator. 871 76

Sodium nitroprusside (SNP) spontaneously produces nitric oxide (NO). In many cell types, this activates the soluble form of the enzyme guanylyl cyclase (GC), resulting in the elevation of cGMP. We herein report the role of NO and cGMP on iodide uptake in primary cultures of calf thyroid cells. Iodide uptake is the limiting step in thyroid hormone biosynthesis and a typical functional parameter. The effect of SNP on this parameter was thus determined. In cells treated with TSH for 72 h, addition of 5 mM SNP for the last 2 h caused a significant inhibition on iodide uptake, with no change in cells not treated with TSH. This action was mimicked by an analogue of cGMP, 8Br-cGMP, and blocked by reduced hemoglobin, thus suggesting that it is mediated by the GC-cGMP pathway. SNP also inhibited the stimulation caused by forskolin or analogues of cAMP, indicating that the effect takes place in this pathway, which would be distal to cAMP generation. The accumulation of radioiodine by thyroid cells is a consequence of the balance between influx and efflux. The studies demonstrate that SNP does not affect iodide efflux, thus revealing that it inhibits the influx.
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PMID:Role of cyclic 3'5' guanosine monophosphate and nitric oxide in the regulation of iodide uptake in calf thyroid cells. 948 90

C-type natriuretic peptide (CNP) and its cognate guanylyl cyclase receptor, the natriuretic peptide receptor B (NPR-B) together constitute a regulatory system that controls cell function via the generation of intracellular cyclic GMP. In this report we have examined the role of cAMP signaling in the regulation of CNP and NPR-B activity in the FRTL-5 rat thyroid follicular cell line. As had been observed earlier with TSH, the cAMP mimetic, dibutyryl cAMP (dbcAMP; 1 mM) induced a significant reduction in CNP-stimulated cGMP generation that was first apparent after 6 h of treatment. The inhibitory effect of dbcAMP on NPR-B was dose dependent, with an EC50 of 0.2 mM. Pretreatment of FRTL-5 cells with either of two protein kinase A (PKA) inhibitors, KT-5720 and H-89, failed to curtail the dbcAMP reduction in NPR-B activity, suggesting that the cAMP pathway leading to inhibition of NPR-B is PKA independent. Whereas either a 30-min or a 24-h treatment with the protein kinase C-activator phorbol myristate acetate failed to alter maximal levels of CNP-stimulated cGMP, a 24-h exposure to the calcium ionophore A23187 reduced CNP-stimulated cGMP to about one-third of control. Pretreatment of FRTL-5 cells with the cell-permeable calcium chelator 1,2 bis(2-aminophenoxy)ethane-N,N,N1,N1-tetraacetic acid, tetraacetoxymethyl ester completely abrogated the cAMP-induced reduction of CNP-stimulated cGMP. Real-time PCR showed no effect of dbcAMP on NPR-B transcript at 3 and 6 h, but indicated a 40% reduction in transcript by dbcAMP at 24 h. In contrast, real-time PCR indicated a 5-fold increase in CNP transcript at 3 h, reaching 15.4-fold above control at 6 h in cells treated with dbcAMP. In addition, immunofluorescence staining of FRTL-5 cells with a specific antibody for CNP-22 showed the presence of cytoplasmic CNP that was up-regulated by incubation with either TSH or dbcAMP. These results suggested that cAMP signaling regulates the natriuretic peptide system in rat thyroid cells by increasing CNP expression, and reducing NPR-B activity. This latter action of cAMP appears to be both PKA independent and calcium dependent, and provides support for a dominant role for calcium in the regulation of NPR-B in the rat thyroid.
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PMID:cAMP inhibits natriuretic peptide receptor-B activity and increases C-type natriuretic peptide in FRTL-5 rat thyroid cells. 1470 41

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