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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper discusses the mechanisms of two basic effects of thyroid hormones on atrial responses to beta-adrenergic agonists, i.e. increased inotropic sensitivity and decreased maximal contractile responsiveness. The increased sensitivity of atria to beta-adrenergic agonists under thyroid hormones appears to be related to increases in beta-adrenoceptor density and Gs/Gi protein ratio, leading to activation of Gs-mediated pathway, but suppression of Gi-mediated pathway of adenylate cyclase regulation. Therefore, the i/c concentrations of cAMP and corresponding inotropic responses achieve their maximums at lower doses of beta-adrenergic agonist. Thyroid hormones also decrease the expression of phospholamban, but increase the expression of sarcoplasmic reticulum Ca2+-pump. As a result, the basal activity of sarcoplasmic reticulum Ca2+-pump increases, but its beta-adrenergic activation through phosphorylation of phospholamban decreases. It is suggested that these changes are causal for decreased maximal inotropic and lusitropic responses of atria to beta-adrenergic agonists.
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PMID:Mechanisms of thyroid hormone control over sensitivity and maximal contractile responsiveness to beta-adrenergic agonists in atria. 974 36

Thyroid hormones are important for neurogenesis and gliogenesis during brain development. We have previously demonstrated that triiodothyronine (T3) treatment induced proliferation in primary culture astrocytes derived from the cerebellum of neonatal rats. Conditioned medium obtained from those T3-treated astrocytes (T3CM) mimicked the effect of hormonal treatment on these cells. Because neuron-glia interaction plays an important role in brain development, we tested the ability of such T3-glial CM to influence neuronal physiology. With that aim, neurons from 19-day embryonic cerebella were cultivated for 24 h in the presence of CM obtained from T3-treated cerebellar astrocytes. Interestingly, the cerebellar neuronal population increased by 60-80% in T3CM. Addition of 5 microM forskolin enhanced the responsiveness of cerebellar neurons to astrocytes T3CM, but it did not interfere with neuronal survival in control medium. Conversely, inhibition of adenylate cyclase by its specific inhibitor, SQ22536, reversed the T3CM effect on neurons. These data strongly suggest that cAMP signal transduction pathways might be implicated in such an event. Analysis of bromodeoxyuridil incorporation revealed that the increase in neuron number in T3CM was partially due to neuron proliferation, because the proliferation index was three times higher in T3CM than in control medium. Neutralizing antibody assays demonstrated that T3CM effects on neurons are due, at least in part, to the presence of tumor necrosis factor-beta and epidermal growth factor. Thus, we report here a novel molecular mechanism of action of thyroid hormone on cerebellar neuronal cells: Thyroid hormone induces astrocytes to secrete growth factors that can interfere with neuronal proliferation via a paracrine pathway.
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PMID:Cerebellar astrocytes treated by thyroid hormone modulate neuronal proliferation. 993 71

Previously, we reported that 5% polyethylene glycol (PEG) (6000) augmented thyroid-stimulating antibody (TSAb)-stimulated cyclic adenosine monophosphate (cAMP) production in porcine thyroid cell (PTC) assay. This augmentation by PEG was specific to TSAb-stimulation. In this study we examined the effects of nonionic hydrophilic polymers such as PEG, polyvinyl alcohol (PVA), and dextran (DEX) on TSAb-stimulated cAMP production. We demonstrated that graded doses of PEG, PVA, and DEX augmented TSAb-stimulated cAMP productions; the prominent augmentations were observed with 5% PEG (20,000), 5% PEG (6000), 6% PEG (4000), 10% PVA, 14% DEX T-250, and 14% DEX T-70. PVA did not augment thyrotropin (TSH)-stimulated cAMP synthesis. Five percent PEG (20,000), 14% DEX T-250, and 14% DEX T-70 augmented TSH-stimulated cAMP synthesis very slightly. PEG, PVA, and DEX had no effects on the cAMP synthesis stimulated by GTPgammaS, forskolin, or pituitary adenylate cyclase activating polypeptide (PACAP), which stimulated adenylate cyclase. We also demonstrated that PEG, PVA, and DEX augmented the cAMP responses stimulated by small amounts (50 microL) of sera from Graves' patients; small amounts (50 microL) of sera could be used instead of purified immunoglobulin G (IgG). This may simplify the TSAb assay. We developed a highly sensitive simplified TSAb assay. PEG weakly augmented TSAb binding to isolated TSH receptor (thyrotropin-binding inhibitor immunoglobulin [TBII] increased slightly). The mechanisms of the augmentations of TSAb-stimulated cAMP productions by PEG, PVA, and DEX is not simply explained by increased binding of TSAb to the receptors. Some factors that enhance TSAb action at the receptor site are suggested.
Thyroid 1999 Mar
PMID:Augmentation of thyroid-stimulating antibody-stimulated cyclic adenosine monophosphate response by polyethylene glycol, polyvinyl alcohol, and dextran; highly sensitive porcine thyroid cell thyroid-stimulating antibody assay. 1021 3

Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared the effects of AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations of iodide than those seen in the NaI-treated cells. The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects.
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PMID:Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism. 1021 20

There has recently been controversy regarding whether the measurement of thyrotropin-binding inhibitory antibodies (TBIAb) is useful in the management of Graves' disease. Another method of assessing Graves' disease by measuring adenylate cyclase activity in thyroid cells, known as thyroid-stimulating antibodies (TSAb), differs from TBIAb not only in terms of assay but also in immunoglobulin type according to recent studies. In this study, the concentrations of TBIAb and TSAb were compared in serial serum samples collected from 29 patients with Graves' hyperthyroidism during 12 months of antithyroid drug therapy. Before therapy, there was a correlation between TBIAb and TSAb (r = 0.59). The radioactive iodine uptake (RAIU) was not significantly correlated with either TBIAb or TSAb (r = 0.20 and r = 0.29, respectively), and the serum free thyroxine (FT4) concentration was also not significantly correlated with either TBIAb or TSAb (r = 0.06 and r = 0.22, respectively). In patients with Graves' ophthalmopathy, TSAb levels were higher than in patients without ophthalmopathy (1015%+/-851% vs. 456%+/-323%, p<0.01), but the TBIAb levels were not significantly different. After antithyroid treatment, TBIAb did not decrease significantly (from 42.1%+/-20.8% to 20.5%+/-19.5%, p = 0.29). On the other hand, TSAb was significantly decreased after 12 months of treatment (from 649%+/-611% to 294%+/-205%, p< 0.05). These findings indicate that TBIAb and TSAb are not identical, and that TSAb has a closer relationship to thyroid function than TBIAb. In the clinical setting, determination of the serum TSAb level may provide a more accurate index of the thyroid status in Graves' disease patients receiving antithyroid therapy.
Thyroid 1999 Aug
PMID:Differences between changes in serum thyrotropin-binding inhibitory antibodies and thyroid-stimulating antibodies in the course of antithyroid drug therapy for Graves' disease. 1048 68

1. This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to beta-adrenoceptor (beta-AR) stimulation. The beta 1- and beta 3-AR mRNAs and proteins were measured by Northern and saturation analyses, respectively. Glycerol production and adenyl cyclase (AC) activity induced by various non-selective and selective beta 1/beta 3-AR agonists and drugs which act distal to the receptor in the signalling cascade were measured in cells from untreated, triiodothyronine (T3)-treated and thyroidectomized rats. 2. The beta 3-AR density was enhanced (72%) by T3-treatment and reduced (50%) by introduction of a hypothyroid state while beta 1-AR number remained unaffected. The beta 1- and beta 3-AR density was correlated with the specific mRNA level in all thyroid status. 3. The lipolytic responses to isoprenaline, noradrenaline (beta 1/beta 3/beta 3-AR agonists) and BRL 37344 (beta 3-AR agonist) were potentiated by 48, 58 and 48%, respectively in hyperthyroidism and reduced by about 80% in hypothyroidism. 4. T3-treatment increased the maximal lipolytic response to the partial beta 3-AR (CGP 12177) and beta 1-AR (xamoterol) agonists by 234 and 260%, respectively, increasing their efficacy (intrinsic activity: 0.95 versus 0.43 and 1.02 versus 0.42). The maximal AC response to these agonists was increased by 84 and 58%, respectively, without changing their efficacy. 5. In the hypothyroid state, the maximal lipolytic and AC responses were decreased with CGP (0.17 +/- 0.03 versus 0.41 +/- 0.08 mumol glycerol/10(6) adipocytes; 0.048 +/- 0.005 versus 0.114 +/- 0.006 pmol cyclic AMP min-1 mg-1) but not changed with xamoterol. 6. The changes in lipolytic responses to postreceptor-acting agents (forskolin, enprofylline and dibutenyl cyclic AMP, (Bu)2cAMP) suggest the modifications on receptor coupling and phosphodiesterase levels in both thyroid states. 7. Thyroid status affects lipolysis by modifying beta 3-AR density and postreceptor events without changes in the beta 1-AR functionality.
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PMID:Regulation of beta 1- and beta 3-adrenergic agonist-stimulated lipolytic response in hyperthyroid and hypothyroid rat white adipocytes. 1071 42

The present work is based on the results of in vivo experiments on rats, which had shown that hypercalcemia had led to morphological and biochemical hyperfunction of thyroid follicular cells. The regulation of the activity of follicular cells should directly, or indirectly via paracrine action of serotonin secreted from parafollicular cells, depend on the presence of calcium ions. The effect of calcium was studied on a cell line of rat follicular cells FRTL-5 (Fischer Rat Thyroid cells in Low serum) using three methods: measuring the quantity of produced cAMP (cyclic adenosine 3',5'-monophosphate), measuring [3H]thymidine incorporation into cell DNA and transmission electron microscopy. Results show that calcium has no effect on cAMP production. Calcium at 1.3 mM, 3 mM, 10 mM, 20 mM and 30 mM concentrations increases [3H]thymidine incorporation into cell DNA when compared with controls without calcium. Calcium at the concentration of 30 mM has no effect on FRTL-5 cell morphology. TSH (thyrotropin) stimulates follicular cells; at higher extracellular concentrations (3 mM, 10 mM, 20 mM, 30 mM), calcium diminishes its effect, presumably by activation of a cAMP phosphodiesterase which disintegrates cAMP and/or by inhibition of adenyl cyclase.
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PMID:The influence of calcium on thyroid follicular cells FRTL-5 in vitro. 1073 Aug 56

Thyroid disease has been associated with the occurrence of pathophysiologic changes in the vasculature that may result in part from altered serum thyroid hormone and serum lipid levels. Thyrotropin (TSH) levels are also altered in thyroid disease, but a direct effect of TSH on vascular smooth muscle has not previously been considered. In the present study, human coronary artery smooth muscle cells (CASMC) were induced into two morphologically distinct forms by culturing in either (1) growth factor supplemented, 0.5% serum medium (SmGM-3) or (2) basal medium (SmBM) plus 10% fetal bovine serum (FBS). Intracellular cyclic adenosine monophosphate (cAMP) accumulation was determined by radioimmunoassay after exposure to increasing doses of bovine TSH. Cells grown in SmBM/10% FBS for 3 days exhibited a dose-dependent increase in intracellular cAMP that reached a level 10 times higher than baseline at the highest dose examined (100 mIU/mL). In contrast, cells grown in SmGM-3 medium exhibited no change in intracellular cAMP on exposure to increasing TSII. Low serum (0.5% FBS) reduced the ability of TSH to stimulate cAMP above the control value in CASMC. Pretreatment of CASMC with either transforming growth factor-beta1 (TGF-beta1) or tumor necrosis factor-alpha (TNF-alpha) lowered basal levels of cAMP production, but did not inhibit the ability of TSH to stimulate cAMP production. Human, but not rat aortic smooth muscle cells in culture also responded to TSH with a significant increase in cAMP. The results of this study suggest that TSH may exert direct effects on vascular smooth muscle mediated by adenylate cyclase activation that could conceivably affect the progression of vascular disease associated with thyroid dysfunction.
Thyroid 2000 Mar
PMID:Thyrotropin regulation of cyclic adenosine monophosphate production in human coronary artery smooth muscle cells. 1077 36

Lithium therapy is the therapeutic mainstay for bipolar disorder and has been associated in the thyroid with euthymic goiter, hyper and hypothyroidism as well as thyroid autoimmune disease. The FRTL-5 cell line is a well known model of thyroid cell physiology, where lithium has been shown to increase 3H-thymidine uptake at concentrations of 2 mM. This mitogenic effect was not associated with adenylate cyclase as measured by cyclic adenosine monophosphate (cAMP) production. The de novo synthesis of cholesterol is an important signal transduction pathway in FRTL-5 cells, where newly synthesized Rho GTPase is geranylgeranylated, enabling membrane localization of the G-protein and subsequent G1 to S-phase transition, resulting from extracellular stimulation. Here we confirm lithium mitogenicity at therapeutically relevant concentrations (1 mM) and demonstrate a lithium-associated accumulation of FRTL-5 cells in S-phase of the cell cycle. These effects could be abolished by Pravastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the rate-limiting enzyme in the formation of intermediates (de novo cholesterol synthesis) required for G-protein prenylation. Pravastatin, similar to lithium, showed no effect on cAMP production either under basal or thyroid stimulating hormone (TSH)-stimulated conditions indicating that de novo cholesterol synthesis is not involved with adenylate cyclase. The inhibitory effect of pravastatin could be overcome by reinitiating de novo cholesterol synthesis. This was achieved by the addition of the cell permeable, first metabolite (mevalonate) after HMG-CoA, which allowed the cycle to continue, leading eventually to protein prenylation, despite the presence of Pravastatin. These novel findings demonstrate lithium involvement in de novo cholesterol synthesis and G-protein prenylation, an important signal transduction pathway in FRTL-5 cells.
Thyroid 2000 Apr
PMID:Mitogenic effect of lithium in FRTL-5 cells can be reversed by blocking de novo cholesterol synthesis and subsequent signal transduction. 1080 58

The liver is an important target organ of thyroid hormone. However, only a limited number of hepatic target genes have been identified, and little is known about the pattern of their regulation by thyroid hormone. We used a quantitative fluorescent cDNA microarray to identify novel hepatic genes regulated by thyroid hormone. Fluorescent-labeled cDNA prepared from hepatic RNA of T3-treated and hypothyroid mice was hybridized to a cDNA microarray, representing 2225 different mouse genes, followed by computer analysis to compare relative changes in gene expression. Fifty five genes, 45 not previously known to be thyroid hormone-responsive genes, were found to be regulated by thyroid hormone. Among them, 14 were positively regulated by thyroid hormone, and unexpectedly, 41 were negatively regulated. The expression of 8 of these genes was confirmed by Northern blot analyses. Thyroid hormone affected gene expression for a diverse range of cellular pathways and functions, including gluconeogenesis, lipogenesis, insulin signaling, adenylate cyclase signaling, cell proliferation, and apoptosis. This is the first application of the microarray technique to study hormonal regulation of gene expression in vivo and should prove to be a powerful tool for future studies of hormone and drug action.
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PMID:Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray. 1089 46


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