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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3H-Labeled inositol phosphate accumulation is observed when prelabeled FRTL-5 cells (a rat thyroid cell line) are exposed to norepinephrine (NE) or TSH. The presence of inositol trisphosphate among the products implicates a phosphodiesterase-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate. The response to NE is much greater than that to TSH. This may be explained by the ability of cAMP to inhibit inositol phosphate accumulation in these cells. The stimulation by NE is inhibited by alpha 1-adrenergic receptor antagonists and is markedly potentiated in medium of reduced Ca2+ concentration. After chronic withdrawal of TSH from the growth medium, the magnitude of the response to NE is considerably reduced; however, there is no substantial shift in the dose-response curve. This reflects the dependency of alpha 1-adrenergic receptor expression on TSH in the FRTL-5 cell. In contrast, the characteristics of inositol phosphate accumulation induced by acute treatment with TSH are similar in cells maintained in the presence or absence of a low concentration of this hormone, and correlate well with the iodide efflux and iodination of thyroglobulin observed in response to TSH. These results support the hypothesis that TSH may mediate certain of its physiological effects through cAMP-independent mechanisms, such as phospholipid/Ca2+ and C-kinase pathways.
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PMID:Norepinephrine and thyroid-stimulating hormone induce inositol phosphate accumulation in FRTL-5 cells. 302 35

Calcium (Ca2+) exchanges were studied in dog thyroid slices incubated in vitro. With 45Ca2+-prelabeled slices, carbamylcholine 10(-7)-10(-5) M (Cchol) induced an important transitory spike efflux, inhibited by procaine and atropine while the stimulated efflux obtained with high concentrations of TSH (10 mU/ml) was progressive and sustained over time. The effects observed with both agents did not require extracellular Ca2+ and were insensitive to verapamil 10(-6)-10(-4) M. Neither dibutyryl (Bu2)-cAMP, nor any agent raising intracellular cAMP (prostaglandin E2, choleratoxin, inhibitors of phosphodiesterases with low concentrations of TSH) were able to reproduce the action of TSH 10 mU/ml, forskolin 10(-5) M being the only exception. Replacement of sodium by choline (+ atropine) in the incubation medium decreased the basal efflux and inhibited the TSH effect. Ouabain 10(-3) M also abolished the TSH-induced Ca2+ efflux, while having no influence on carbamylcholine action. TSH 10 mU/ml and 1 mU/ml, Bu2-cAMP 10(-3) M, choleratoxin and prostaglandin E2 with inhibitors of phosphodiesterase decreased the total 45Ca2+ uptake of the slices, while no effect of Cchol could be detected on this parameter. The results obtained suggest that (1) Cchol and TSH stimulate 45Ca2+ efflux from dog thyroid slices with different kinetics, by mobilization of intracellular Ca2+ stores; (2) this effect of TSH is not mediated by cAMP; (3) independently TSH at low concentrations (1 mU/ml), through cAMP, decreased 45Ca2+ uptake; this suggests that increased 45Ca2+ efflux and decreased uptake result from different mechanisms, as has been described for iodide exchange in FRTL-5 cells.
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PMID:Regulation of calcium fluxes in the thyroid. 303 26

TSH is a trophic factor for cultured rat thyroid cells (FRTL-5). In the present study we have investigated the mechanism by which TSH promotes cell growth and evaluated the possible role of the adenylate cyclase (AC)-cAMP system in this process. The mitogenic activity of several agents was evaluated by measuring their effect on cell number or 3H-thymidine incorporation into DNA. Forskolin and cholera toxin, two potent and specific activators of the AC, induced a dose dependent increase of 3H-thymidine incorporation. The maximal stimulation, observed at concentrations of 10 microM and 10 ng/ml, respectively, was beta 80% of that obtained with optimal concentrations of TSH. A similar effect was obtained with a Graves' IgG preparation (0.2 mg/ml) able to stimulate the thyroid AC or with 3-isobutyl-1-methyl-xanthine (IBMX, 0.5 mM), a phosphodiesterase inhibitor. 8-bromo cAMP (0.5 mM), a cAMP analog, also stimulated 3H-thymidine incorporation, and its potency was approximately 60% of that of TSH. Similar results were obtained when the mitogenic activity of these compounds was evaluated by cell number. Norepinephrine (NE, 10 microM), although devoid of AC stimulatory activity in these cells, also stimulated 3H-thymidine incorporation, but its potency was only 20-30% of that of TSH. Indomethacin (100 microM), an inhibitor of phospholipid and arachidonic acid metabolism, was able to inhibit the stimulatory effect of NE (84%), and to a lesser extent of TSH (63%) and cholera toxin, had minor effect on forskolin (24%), IBMX (16%) and Graves' IgG (8%), and no effect on 8-bromo cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of the adenylate cyclase-cAMP system on TSH-stimulated thyroid cell growth. 303 75

A variety of cyclic nucleotide analogs and other agents that affect thyroid cyclic nucleotide metabolism were used to investigate the role of cAMP and cGMP in regulating nuclear protein phosphorylation in calf thyroid slices labeled in vitro with [32P]orthophosphate. Two major groups of acid-soluble proteins were studied. Group I consisted of proteins whose phosphorylation is stimulated by TSH [histones H1 and H3, high mobility group (HMG) protein 14, and the HMG 14/17-like protein PS.3]; group II included representatives of a spectrum of proteins whose phosphorylation is unaffected by TSH (histones H2A, H2B, and H4, HMG 17, the HMG 14/17-like protein PS.2, and the nonhistone protein AS.1). The effects of TSH (50 mU/ml) on the 32P labeling of group I proteins were partially reproduced by (Bu)2cAMP (1 mM), 8-bromo-cAMP (1 mM), and butyrate (2 mM), and closely mimicked by 8-(4-chlorophenylthio)cAMP (1 mM), forskolin (25 microM), and butyrate (10 mM). (Bu)2cGMP (1 mM), 8-bromo-cGMP (1 mM), and carbachol (50 microM) had no effect on protein phosphorylation. NaNO2 (20 mM), which markedly increases cGMP concentration in calf thyroid slices, decreased the 32P labeling of group I proteins and also affected, to varying extents, the phosphorylation of the group II proteins. The phosphodiesterase inhibitor methylisobutylxanthine (0.5 mM) had generally minor effects on 32P labeling; however, it did counteract the effects of NaNO2 on group I protein phosphorylation. Our results provide strong support for the hypothesis that TSH-dependent phosphorylation of group I proteins is mediated by cAMP, but they provide little evidence of cGMP regulation of histone or HMG protein phosphorylation.
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PMID:Histone and high mobility group protein phosphorylation in the thyroid: regulation by cyclic nucleotides. 620 23

When thyroid cells in vitro are stimulated by TSH for 2 h cyclic AMP (cAMP) is synthesized at a high rate during the first 25 min of stimulation, thereafter at a lower rate. The mechanism for this reduction of adenyl cyclase activity was studied in vitro using mouse thyroid tissue. As some of the cAMP formed is released from the cells the sum of cAMP in tissue and incubation medium was studied and considered to reflect the accumulated cAMP synthesis as breakdown synthesis as breakdown by phosphodiesterase was minimized by 1 mM theophylline. The TSH stimulated tissue did not release any adenyl cyclase inhibiting factor into the incubation medium. Cycloheximide, 5 micrograms/ml, enhanced the cAMP response to a single or repeated stimulation by TSH. Its effect was visible after 25 min of incubation and remained at about the same size for 2 h, but the levelling off of cAMP synthesis was not prevented but took place at a higher level. The effect of puromycin, 500 microgram/ml, was similar to that of cycloheximide. Also actinomycin D, 1 microgram/ml, enhanced the cAMP response to TSH. It is concluded that a protein synthesis dependent inhibitor of adenyl cyclase is activated by TSH, but it accounts only for a minor part of the adenyl cyclase inhibition that takes place in the later part of a TSH stimulation of the thyroid. Additional adenyl cyclase inhibiting mechanisms must be considered.
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PMID:Effect of inhibition of protein synthesis on thyroid cyclic AMP accumulation in vitro. 626 27

The evidence is reviewed that a desensitization to thyrotropin is of three distinct types. Type 1 is proximal to the production of cyclic AMP and is manifested by a fall of cyclic AMP concentration in the thyroid tissue despite the continued presence of TSH or phosphodiesterase inhibitors in the medium. Type 2 is distal to this event and involves the metabolic effects of TSH mediated by cyclic AMP such as colloid droplet formation, iodide organification and, in dog thyroid, glucose oxidation. All these effects may be due to a reduced amount of cyclic AMP which is not capable of stimulation the protein kinase. They may be prevented by a pre-exposure to similar concentrations of TSH and cannot be overcome by other stimulators acting through the same adenylate cyclase-cyclic AMP pathway. Type 3 involves the processes not regulated by cyclic AMP. Thus, a desensitization of thyroid tissue by pre-exposure to TSH results in a reduced response of phospholipid turnover, a process not mediated by cyclic AMP, either to homologous (TSH) or heterologous (acetylcholine) stimulation.
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PMID:Three types of desensitization of metabolic responses to thyrotropin in thyroid tissue: a review. 629 98

Forskolin (40 microM) stimulated adenylate cyclase activities of bovine thyroid plasma membranes without the addition of guanine nucleotides. GDP had little effect on the forskolin-stimulated adenylate cyclase activity while Gpp[NH]p (0.1-1.0 microM) decreased it. In the presence of TSH (10 mU/0.11), Gpp[NH]p no longer caused inhibition. Forskolin did not affect phosphodiesterase activities of thyroid homogenates. Forskolin (10 microM) rapidly increased cAMP levels in bovine thyroid slices both in the absence and presence of a phosphodiesterase inhibitor. The effect of TSH (50 mU/ml) on cAMP levels was additive or greater than additive to that of forskolin. An initial 2-h incubation of slices with forskolin did not decrease their subsequent cAMP responses to either forskolin and/or TSH while similar treatment of slices with TSH induced desensitization of the cAMP response to TSH, but not to forskolin. Forskolin (10 microM) as well as TSH (50 mU/ml) activated cAMP-dependent protein kinase of slices in the absence of a phosphodiesterase inhibitor. Although forskolin activated the adenylate cyclase cAMP system, it did not stimulate iodide organification or glucose oxidation, effects which have been attributed to cAMP. In fact, forskolin inhibited these parameters and 32P incorporation into phospholipids as well as their stimulation by TSH. These results indicate that an increase in cAMP levels and cAMP-dependent protein kinase activity in thyroid slices may not necessarily reproduce the effects of TSH on the thyroid.
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PMID:Effects of forskolin on adenylate cyclase, cyclic AMP, protein kinase and intermediary metabolism of the thyroid gland. 629 78

The effect of TSH on the adenylate cyclase-cAMP system and in vitro iodothyronine release, together with the iodothyronine and iodine content of 19s thyroglobulin, were studied in seven clinically euthyroid patients with autonomous thyroid nodules. Basal cAMP and cGMP content together with phosphodiesterase and protein-kinase activities were normal in nodular, and suppressed in extranodular tissue. TSH-dependent cAMP accumulation was reduced in nodular tissue, but normal in the suppressed extranodular tissue. In vitro TSH-dependent iodothyronine release from nodular and extranodular tissue was absent. Thyroxine and iodine content of thyroglobulin extracted from nodular tissue was reduced, while triiodothyronine content was normal but with a low T4/T3 ratio. In extranodular tissue T3, T4 and iodine contents were reduced. In conclusion, autonomous thyroid nodules produced a poorly iodinated thyroglobulin leading to preferential T3 secretion with increased circulating free thyroid hormones even in clinically euthyroid patients.
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PMID:Effects of TSH on cAMP levels and thyroid hormone release in human thyroid 'autonomous' nodules: relationship with iodothyronine and iodine content in thyroglobulin. 629 22

We have analysed immunoassayable thyroglobulin (hTg) secretion from both normal and abnormal isolated human thyroid cells after short-term monolayer culture. All cells were sensitive to more than 10 microU/ml bTSH when assessed by intracellular cyclic AMP accumulation in the presence of a phosphodiesterase inhibitor. hTg release was stimulated in all cells by bTSH in a dose related manner and with a detectable response within 24 h. Basal hTg secretion rates were greater in cells derived from benign follicular adenomata (range 1.1-2.2 ng/10(5) cells/h, n = 4) than in normal human thyroid cells (range 0.1-0.65 ng). Therefore it appears likely that hTg secretion by adenomatous thyroid cells was a likely contributor to increased serum hTg in patients with single follicular adenomata. We conclude that simple human thyroid cell monolayers have potential for the further study of hTg secretion and its control by TSH.
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PMID:Thyroglobulin secretion by human thyroid cells after monolayer culture--comparison of normal and adenomatous cells. 647 29

The production of hydrogen peroxide (H2O2) as an essential process for iodide organification is a key reaction in TSH-induced thyroid hormone synthesis. Here we characterize the signal transduction pathway involved in TSH-induced H2O2 production in FRTL-5 thyroid cells. At higher than 1 nM TSH, N6-(L-2-phenylisopropyl)adenosine (PIA), an adenosine receptor agonist having, by itself, no influence on H2O2 generation, potentiated this TSH action, whereas the TSH increase and PIA addition reduced cAMP accumulation. RO 20-1724, a phosphodiesterase inhibitor, amplified the TSH-induced cAMP accumulation, but did not change H2O2 generation in the whole range of TSH used. Ca(2+)-mobilizing agonists, GTP and ATP, also induced H2O2 production without stimulating cAMP accumulation. Chelation of intracellular Ca2+ markedly inhibited the TSH action, but intracellular Ca2+ increases by either thapsigargin or ionomycin mimicking it. All of the findings show the participation of Ca2+, but not cAMP, in the action of TSH. Desensitization of protein kinase-C (PKC) did not influence the receptor-mediated H2O2 production, suggesting the reduced importance of PKC activation compared to Ca2+ signaling to the reaction. A rise in intracellular Ca2+ independent of receptor activation also induced H2O2 production as well as arachidonate release, and both were potentiated by PIA. In addition, inhibitors of phospholipase-A2 and the arachidonate metabolic pathway depressed H2O2 generation, suggesting the participation of an arachidonate cascade in the Ca(2+)-dependent H2O2 production. Lipoxygenase inhibitors depressed the Ca2+ action without influencing arachidonate release, suggesting the involvement of a lipoxygenase product(s) of arachidonate in the Ca(2+)-signaling mechanism. In conclusion, in FRTL-5 cells, TSH-induced H2O2 production is mediated not by cAMP, but by the phospholipase-C/Ca2+ cascade, possibly followed by the Ca(2+)-dependent phospholipase-A2/arachidonate cascade. PIA amplifies TSH-induced H2O2 production at the steps of phospholipase-C and phospholipase-A2 activation in a pertussis toxin-sensitive manner.
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PMID:Thyrotropin-induced hydrogen peroxide production in FRTL-5 thyroid cells is mediated not by adenosine 3',5'-monophosphate, but by Ca2+ signaling followed by phospholipase-A2 activation and potentiated by an adenosine derivative. 782 20


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