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)

Adipose-tissue triacylglycerol is the major energy store in man. The physiological importance and biochemical mechanism of the hormonal control of lipolysis in white adipose tissue is reviewed. Rates of lipolysis and fatty acid release observed when adipose tissue is incubated in vitro are compared with rates of triacylglycerol turnover in man. It appears that enhanced rates of lipolysis in vivo, for example during fasting and exercise, may be a substantial fraction of the maximum obtainable by hormone stimulation in vitro. There is considerable species variation in the hormonal sensitivity of adipose tissue. Some hormones that stimulate lipolysis in vitro may not be significant lipolytic agents at physiological concentrations in vivo. In man and rat, the most important acutely acting lipolytic and anti-lipolytic hormones are catecholamines and insulin respectively. The sympathetic nervous system may play a role at least as important as circulating catecholamines in the mobilization of stored triacylglycerol. The effects of acute lipolytic hormones are modulated in the long term by corticosteroids and thyroid hormone. Stimulation of lipolysis is believed to be mediated by the increased intracellular cyclic AMP concentration that occurs after interaction of hormones with specific receptors in the plasma membrane. The properties of membrane receptors, adenylate cyclase, cyclic AMP phosphodiesterase, cyclic AMP-dependent protein kinase and triacylglycerol lipase, as studied in rat and human adipose tissue, are discussed. Several features of the action of lipolytic hormones in vitro are difficult to account for by the hypothesis that cyclic AMP is the only "second messenger" regulating lipase activity. These include anomalous effects of hormones at high concentrations and the possible existence of feedback inhibition limiting the accumulation of cyclic AMP and the stimulation of lipolysis. The mechanism of the anti-lipolytic action of insulin is at present unknown.
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PMID:Hormonal control of adipose-tissue lipolysis. 21 67

Earlier studies indicated that initial exposure of thyroid slices to thyrotropin diminished responsiveness of the adenylate cyclase-cyclic AMP system, glucose oxidation, and (32)P(i) incorporation into phospholipids upon readdition of the hormone. The present studies demonstrate that slices from dog, beef, and human thyroid glands initially incubated with thyrotropin (TSH) were less responsive to subsequent addition of the hormone when organification of iodide was examined. Increasing the amount of TSH did not overcome the refractoriness induced by the initial exposure to the hormone. Furthermore, the stimulatory effects of dibutyryl cyclic AMP and prostagladin E(1) were abolished in slices previously incubated with TSH. Development of such refractoriness did not depend upon new protein synthesis and was not abolished by 1 mM prophylthiouracil in the first incubation. Addition of 0.1 muM thyroxine or triiodothyronine or 1.5 muM iodide during all three incubations did not modify the response to TSH, added for the first time in the third incubation. However, 1 mM iodide in the buffer during all three incubations inhibited the response to TSH during the third incubation. During the refractory period, effects of TSH on colloid droplet formation were also diminished. The in vivo effect of TSH on serum l- triiodothyronine in rats was significantly reduced when the rats had been injected with TSH 8 h earlier. These studies demonstrate that TSH-induced refractoriness also includes effects on organification of iodine and secretion of thyroid hormone. The results cannot be adequately explained by unresponsiveness of adenylate cyclase because effects of dibutyryl cyclic AMP and prostagladin E(1) were also inhibited by prior exposure to TSH.
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PMID:In vitro and in vivo refractoriness to thyrotropin stimulation of iodine organification and thyroid hormone secretion. 22 45

We studied the effects of administration of dexamethasone, 2 mg orally every 6 hr for 4 doses, on circulating thyroid hormone levels in hyperthyroid Graves' disease patients and in normal subjects. Serum triiodothyronine (T3), thyroxine (T4) and thyroglobulin (Tg) fell significantly below baseline values within 24 to 48 h after the first dose of dexamethasone in hyperthyroid patients; the values returned to or toward baseline levels in the subsequent 5 to 6 days. Serum T3 fell transiently in normals but to a much smaller degree than in hyperthyroid patients; T4 and Tg showed no significant change. Dexamethasone had ni inhibitory effect on the thyroid response to exogenous TSH in the hyperthyroid patients. Studies in vitro demonstrated lack of any appreciable effect by dexamethasone or hydrocortisone on stimulation of human thyroid adenyl cyclase by TSH or immunoglobulin G(IgG) from patient with Graves' disease. The fall in serum T3 without a change in serum T4 in normals suggested an effect of dexamethasone on peripheral conversion of T4 to T3. However, the markedly greater, more persistent drop in T3 in the hyperthyroid patients, as well as the associated drop in T4 and Tg, suggested an additional effect of dexamethasone administration on thyroid secretion in these patients. Preservation of thyroidal response to TSH during dexamethasone administration both in vivo and in vitro indicated that dexamethasone had not impaired thyroidal cellular processes per se. The data were consistent with an effect of dexamethasone on thyroid stimulator. The putative stimulator does not appear to be normal pituitary thyrotropin (TSH), since TSH was not detected in serum of anyof the patients studied. Additionally, the changes observed were too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator. The data are consistent with the possibility that there may be a non-TSH non-IgG thyroid stimulator in Graves' disease.
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PMID:Acute effects of corticosteroids on thyroid activity in Graves' disease. 117 32

Cardiac myosin heavy chain expression undergoes a perinatal transition from predominance of beta-MHC to alpha-MHC. In the current study, we tested the effects of glucocorticoids in this early transition period, by treating pregnant rats with dexamethasone on gestational days 17, 18 and 19, using doses below (0.05 mg/kg), at (0.2 mg/kg) or above (0.8 mg/kg) the threshold for growth retardation. Cardiac MHC isoforms were resolved with a denaturing SDS-PAGE system, followed by quantitative densitometry. In normal animals alpha-MHC was only 10% of the total on gestational day 18 but rose to 35% by postnatal day 1, and to 95% by the end of the first month postpartum. During the early phase of this transition, the lowest dose of dexamethasone significantly promoted alpha-MHC expression without inhibiting body or heart growth; regression analysis indicated a 40% increase in the slope of MHC isoform transition with respect to tissue weight. In contrast, the higher, growth-retarding doses of dexamethasone either failed to enhance alpha-MHC expression or caused biphasic changes, with inhibition at ages corresponding to the onset of weight deficits; regression analysis indicated that the effects of the higher doses on MHC could all be accounted for by changes in tissue weight. Glucocorticoid levels rise substantially in the period surrounding parturition, and serve to program the development and coupling of adenylate cyclase to membrane receptors; because adenylate cyclase has been shown to elicit the beta-MHC to alpha-MHC transition in vitro, our results suggest that glucocorticoids, along with thyroid hormone and beta-adrenergic stimulation, influence the ontogenetic program of MHC isoform transition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucocorticoids accelerate the ontogenetic transition of cardiac ventricular myosin heavy-chain isoform expression in the rat: promotion by prenatal exposure to a low dose of dexamethasone. 128 77

In mature animals, thyroid hormone is permissive for beta adrenergic receptor expression and adrenergic control of adenylate cyclase. To determine if endogenous thyroid hormones play a similar role in the development of receptors and transduction mechanisms, we administered propylthiouracil perinatally to rat dams and pups from gestational day 17 through postnatal day 5. Circulating thyroid hormones were completely suppressed through postnatal day 10 and then rose to only slightly subnormal values by the 3rd to 4th postnatal week. In the heart, hypothyroidism completely suppressed the initial development of beta adrenergic receptor binding sites, with recovery paralleling the return of thyroid hormone levels. In contrast, development of basal and isoproterenol-stimulated adenylate cyclase activity showed more lasting deficiencies with a delayed onset corresponding to general growth impairment; however, forskolin-stimulated adenylate cyclase developed in a nearly normal pattern. Effects on development of renal beta receptors and adenylate cyclase were of smaller magnitude and comprised only the delayed onset phase; receptor deficiencies appeared after 10 days and adverse effects on adenylate cyclase were limited to the isoproterenol-sensitive component, consisting of a shift of the ontogenetic peak to later ages. Endogenous thyroid hormones thus contribute two distinct factors to beta receptor/adenylate cyclase development: they are obligatory for cardiac beta receptor development, but also, in parallel with general effects on growth and development, serve to program the ontogeny of transduction factors linking the receptors to adenylate cyclase. The predominance of propylthiouracil effects on isoproterenol-stimulated adenylate cyclase but not on enzymatic responses to forskolin suggests that thyroid hormones may be controlling the development of regulatory G-proteins.
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PMID:Thyroid hormone regulates ontogeny of beta adrenergic receptors and adenylate cyclase in rat heart and kidney: effects of propylthiouracil-induced perinatal hypothyroidism. 131 78

The positive inotropic effects of thyroid hormone in the heart, increased force and velocity of contraction have been mostly attributed to modulation of myosin ATPase isoenzymes (V1, V2 and V3), and sarcoplasmic reticulum Ca2+ pumping activity. In addition, we have suggested that the effects on ventricular contraction result from a thyroid hormone-induced increase in L-type Ca2+ current (ICa,L). Due to the central role of ICa,L in excitation-contraction coupling, we studied mechanisms whereby thyroid hormone augments this current. Since thyroid hormone modulates adenylate cyclase activity in various tissues, we tested the hypothesis that the hormone activates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A activation, Ca2+ channel phosphorylation and increased ICa,L. We therefore stimulated or inhibited different sites along the "adenylate cyclase cascade", and measured ICa,L and isometric twitch in ventricular myocytes and papillary muscles from euthyroid and hyperthyroid guinea pigs. Our major findings were as follows. In euthyroid myocytes, 0.1 microM isoproterenol (Iso) increased ICa,L (at VM = 0 mV) from -7.04 +/- 0.72 to -22.26 +/- 1.88 pA/pF, P < 0.05, while in hyperthyroid myocytes (ICa,L = -21.48 +/- 2.94 pA/pF), Iso was ineffective. In euthyroid myocytes, intracellular application of cAMP (50 microM) was as potent as Iso, but ineffective in hyperthyroid myocytes. In hyperthyroid myocytes, a protein kinase A inhibitor (2 microM) lowered ICa,L from -26.82 +/- 1.54 to -10.17 +/- 1.70 pApF (P < 0.05), but had no effect in euthyroid myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of hyperthyroidism-induced modulation of the L-type Ca2+ current in guinea pig ventricular myocytes. 133 56

Cardiac myosin heavy chain (MHC) expression undergoes an ontogenetic transition from beta to alpha MHC isoforms. Although thyroid hormone plays a role in this change, the timing of the events suggests the participation of other factors. Using a new, denaturing SDS-PAGE procedure that cleanly resolves the beta and alpha heavy chains, we have assessed the role of beta-adrenergic stimulation on this transition in fetal and neonatal rat hearts. In control animals at embryonic day 20, less than 15% of the MHC was the alpha-form, and the proportion increased to approximately 35% by postnatal day 1 and to 80% by postnatal day 8. Although catecholamine levels rise abruptly at birth, and cyclic AMP levels increase the expression of alpha-MHC in vitro, neither premature beta-adrenergic stimulation (maternal treatment with terbutaline on embryonic days 17, 18 and 19) nor continuous prenatal blockade of beta-receptors (maternal propranolol infusions from embryonic day 7 onward) influenced the developmental profile. Because beta-receptors in fetal and neonatal heart are functionally linked to adenylate cyclase, and cyclic AMP has been shown to promote the expression of alpha-MHC, the lack of effect of terbutaline or propranolol suggests that activation of adenylate cyclase through fetal cardiac beta-receptors is not sufficient to mediate the switchover without participation of other factors, such as thyroid or steroid hormones, or hypoxia.
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PMID:Ontogenetic transition of cardiac myosin heavy chain isoforms in rat ventricle: effects of fetal exposure to beta-adrenergic agonists or antagonists. 135 26

We have demonstrated previously that a variety of agents including corticosteroids, thyroid hormone, cationophores, methylxanthines, and analogues of cAMP--all of which have diversified functions in various tissues--elevate cellular angiotensin converting enzyme (ACE) activity of bovine endothelial cells in culture. In addition to these agents, we have now found that direct and receptor-mediated stimulators of adenylate cyclase, i.e., forskolin and cholera toxin, increase cellular ACE activity after 48 h incubation in culture. In an attempt to search out a more unifying concept of these stimulatory effects, we have further investigated the roles of second messengers in the stimulatory actions. Ca2+ ionophore A23187 produced significant increases in both intracellular Ca2+ and ACE of endothelial cells. In contrast to Ca2+ ionophore, agents that transiently mobilize Ca2+ from intracellular reserves such as bradykinin, acetylcholine, and ATP have no effect on the level of cellular ACE. Representative agents that elevate cellular cAMP (e.g., isobutyl methylxanthine [IBMX] and dibutyryl cAMP) elevated cellular ACE, but the slightly increased [Ca2+]i produced by these agents did not reach statistical significance. While IBMX, cholera toxin, and forskolin elevated cellular cAMP, other ACE stimulatory agents (hormones and cationophores) had no effect on cAMP. Ca2+ ionophore and the agents that elevated intracellular cAMP potentiated the effect of dexamethasone, thyroid hormone, and aldosterone in elevating cellular ACE activity. Increases in ACE activity produced by all stimulants were inhibited by the presence of 10-50 nM ouabain in the culture medium. Inhibition of ACE elevation by oubain was reversed by increasing the extracellular [K+], thereby implicating Na+, K(+)-ATPase in the ACE regulatory mechanism. These results support the presence of multiple independent mechanisms for the regulation of cellular ACE. In addition to possible involvement of intracellular Ca(2+)- and cAMP-dependent pathways, ACE is also increased by corticosteroids and thyroid hormone through mechanisms unrelated to Ca2+ and cAMP.
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PMID:Involvement of second messenger systems in stimulation of angiotensin converting enzyme of bovine endothelial cells. 165 91

In mature animals, thyroid hormone produces parallel up-regulation of beta-adrenergic receptor binding sites and their linkage to adenylate cyclase; during development, these same processes may be critical in establishing the set-point for subsequent adrenergic reactivity. In the current study, we administered triiodothyronine to neonatal rats for the first five days postpartum and evaluated [125I]pindolol binding capabilities and adenylate cyclase activity in membrane preparations from heart and kidney. In the heart, hyperthyroidism elicited an initial increase in receptor density, with subsequent deficits and an eventual return to normal values by young adulthood. In contrast, the ability of isoproterenol, a beta-adrenergic agonist, to stimulate adenylate cyclase was enhanced regardless of whether receptor numbers were increased or decreased; the same effects were also present for basal adenylate cyclase activity and non-receptor-mediated stimulation by forskolin. Enhanced cyclase activity involved both increases in the magnitude of response as well as accelerated onset of the postweaning peak of enzyme activity, results which suggest a direct impact of thyroid status on the ontogenetic expression of adenylate cyclase itself. The kidney, which possesses less efficient beta-receptor coupling to adenylate cyclase in the neonate, was less drastically affected by triiodothyronine for either beta-receptor binding sites or enzyme activity. As we had previously shown that neonatal hyperthyroidism uncouples beta-receptors from growth-related enzymes, such as ornithine decarboxylase, we also evaluated whether the promotion of adenylate cyclase responses was mechanistically linked to effect on ornithine decarboxylase; administration of cyclic AMP analogs to 5 days-old rats led to inhibition of the enzyme in the heart, whereas the same treatment in 9 days-old animals was ineffective. These data suggest that thyroid hormone differentially regulates the development of beta-receptors as well as adenylate cyclase and ornithine decarboxylase, with preferential effects on tissues, such as the heart, that already possess efficient linkage of the receptors to cell transduction mechanisms at birth.
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PMID:Thyroid hormone differentially regulates development of beta-adrenergic receptors, adenylate cyclase and ornithine decarboxylase in rat heart and kidney. 166 5

The concept of using thyroid-stimulating hormone (TSH) receptor antagonists in the management of Graves' disease is intriguing. Therefore, we investigated a TSH receptor antagonist derived from human chorionic gonadotropin (hCG) with respect to TSH receptor binding, adenylate cyclase activity, thyroid hormone release, and HLA class II antigen expression in vitro and in an in vivo model. A variant of hCG, asialoagalacto-hCG, like asialo-hCG and unlike hCG itself, inhibited both 125I-bTSH binding and cAMP response to bTSH in human thyroid membranes. However, like intact or deglycosylated hCG and unlike asialo-hCG, asialoagalacto-hCG displayed a limited affinity for hepatic asialoglycoprotein receptors, a likely marker for its in vivo turnover rate. It proved capable of inhibiting bTSH-stimulated thyroid hormone release in human thyroid slices as well as in the nude mouse bearing human thyroid transplants. It also prevented bTSH induced hypertrophy of transplanted thyrocytes. Further, HLA-DR expression induced by bTSH in the presence of gamma-interferon on human thyrocytes was inhibited. In conclusion, we present evidence that asialogalacto-hCG antagonizes bTSH actions on thyroid function and HLA-DR expression in human thyroid in vitro and, more importantly, in an in vivo model. Hence, the hCG variant described here or similar agents should warrant further exploration in the study and treatment of Graves' disease.
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PMID:Asialoagalacto-human chorionic gonadotropin, a carbohydrate-modified variant of human chorionic gonadotropin, antagonizes the stimulatory actions of bovine thyroid-stimulating hormone on thyroid function and HLA-DR expression in human thyroid in vitro and in vivo. 175 54


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