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)

The present study was designed to describe the relationships among thyroid status, myocardial growth and myocardial beta-adrenergic receptors in the developing rat ventricle. In normal rat myocardium the beta-adrenergic binding capacity (Bmax) for (-)-[3H] DHA decreased with increasing age and heart size. In order to determine the effect of thyroid status on ventricular growth characteristics and beta-adrenergic receptors, animals were rendered: (1) hypothyroid with propylthiouracil (PTU), (2) euthyroid with PTU and daily thyroxine (T4) replacement, (3) hyperthyroid for several days with daily thyroxine injections or (4) normal controls with sham saline injections. Growth characteristics were similar in euthyroid and normal rat myocardium; ventricular weight, protein and DNA content were similar at postnatal days 5, 15 and 28. Growth in hypothyroid pups was normal until postnatal day 14 at which time the heart weight and protein content were significantly lower than in normal or euthyroid pups, whereas the number of beta-adrenergic receptors was decreased in hypothyroid myocardium at all ages studied. On postnatal day 5 the (-)-[3H]DHA binding (Bmax) was 37 +/- 9 in hypothyroid myocardium compared to 63 +/- 8 fmole per mg protein mean +/- S.D. in euthyroid myocardium. The function of the beta-adrenergic receptors was also decreased in hypothyroid as compared to euthyroid or normal myocardium as demonstrated by a decrease in maximal catecholamine sensitive adenylate cyclase activity in myocardial membranes at 28 days of age. Treatment of hypothyroid or normal pups with T4 resulted in an increase in heart size, protein content and beta-adrenergic receptors. Ventricular DNA content, which describes hyperplastic growth, was not decreased in hypothyroid rats demonstrating that postnatal hypertrophic but not hyperplastic ventricular growth is dependent on thyroid hormone.
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PMID:beta-Adrenergic receptors and catecholamine sensitive adenylate cyclase in developing rat ventricular myocardium: effect of thyroid status. 628 64

Adrenergic mechanisms may be important in the symptomatic manifestations of hyperthyroidism. The chronic administration of thyroid hormone also results in cardiac hypertrophy and increased numbers of beta-adrenergic receptors in cardiac membranes. The roles of adrenergic mechanisms in the initiation and perpetuation of this hypertrophy has been open to speculation. Rats treated chronically with L-thyroxin were sacrificed after 7 days of treatment and 1-4 days after cessation of treatment. Hearts were removed and weighed and norepinephrine measured. In other groups of identically treated rats, membranes were prepared from the left ventricle for in vitro measurements of beta-adrenergic receptor characteristics and adenyl cyclase activity. Regression of cardiac hypertrophy with a decrease in receptor number to control values was seen as early as 2 days after stopping thyroxine. Cardiac norepinephrine concentrations had also returned to control values at this time. Displacement of bound [H3] dihydroalprenolol by isoproterenol was not changed from control. Basal and isoproterenol stimulated adenyl cyclase activity was not changed by thyroxine administration or its cessation. The rapid reversal of the increased beta-adrenergic receptor number and cardiac hypertrophy raises the possibility that thyroid hormone may play a regulatory role in cardiac function. Although the enhancement of myocardial contractility by thyroid hormone may be mediated through cardiac hypertrophy this effect of thyroid hormone is independent of the catecholamine sensitive adenyl cyclase system.
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PMID:Regression of thyroid hormone induced cardiac hypertrophy: effect on cardiac beta receptors and adenyl cyclase activity. 630 78

A detailed review has been conducted of studies addressing dressing the subject of the influence of thyroid hormone on alpha- and beta-adrenergic receptors and adrenergic responsiveness in a wide range of experimental animals and tissues. The studies summarized in the present article have been restricted to those in which explicit measurements of receptor number were made by the use of appropriate radioligands. Particular emphasis is given to an examination of the relationship between thyroid hormone-induced changes in alpha- and beta-adrenergic receptor number and accompanying changes in adenylate cyclase activity and more distal adrenergic responses. Although in many instances thyroid hormone-induced changes in receptor number are reflected in coordinate changes in adrenergic sensitivity, this is shown to be by no means uniformly the case. In contrasting instances, modifications at other more distal sites in the sequence of events mediating catecholamine hormone action are responsible for biochemical and physiological changes in catecholamine responsiveness induced by thyroid hormone.
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PMID:The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. 631 68

The effect of streptozotocin-induced diabetes on the beta-adrenergic receptor-coupled adenylate cyclase was studied in rat heart particulate fractions. Streptozotocin treatment decreased the number of myocardial beta-adrenergic receptors by 34% with no change in the apparent affinity of these receptors for [3H]dihydroalprenolol. The maximal isoproterenol-activated accumulation of cAMP in streptozotocin-treated rat hearts was decreased by only 10%. Insulin administration to streptozotocin-treated rats increased the number of myocardial beta-adrenergic receptors to near or above control levels. Administration of L-T4 to streptozotocin-treated rats had the same effect. Total T4, free T4, and total T3 levels were all significantly decreased in the diabetic animals. Administration of insulin to streptozotocin-treated rats increased the serum thyroid hormone levels toward or above the levels found in control animals. Streptozotocin-induced diabetes had no significant effect on cardiac beta-adrenergic receptor number in thyroidectomized rats. Insulin did not elevate cardiac beta-adrenergic receptor number in thyroidectomized diabetic rats. The decrease in the number of myocardial beta-adrenergic receptors occurring in diabetes mellitus is probably mediated through thyroid hormones.
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PMID:Decreased beta-adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones. 632 44

The thyrotropin (TSH) receptor has been proposed to be composed of a membrane glycoprotein and a membrane ganglioside, the former important in high affinity recognition, the latter vital for message coupling to the adenylate cyclase system. The present study used two approaches, formation of antireceptor monoclonal antibodies and reconstitution, to validate the model and further examine the role of the ganglioside. Three kinds of monoclonal antireceptor antibodies are defined. One group which inhibits TSH binding and TSH functions, i.e., TSH-stimulated adenylate cyclase activity, iodide uptake, and thyroid hormone release, is shown to be directed against the glycoprotein component of the receptor. The second group includes antibodies which mimic TSH in all stimulatory actions, are competitive agonists of TSH, are equivalent to thyroid stimulating antibodies in the sera of patients with Graves' disease, and are directed against the ganglioside component of the receptor. These stimulating monoclonal antibodies are directed against a minor ganglioside membrane component which fractionates as a disialoganglioside. When this ganglioside is incorporated into 1-8 thyroid cells which have a correlated ganglioside deficiency and TSH receptor defect, reconstitution of TSH stimulated adenylate cyclase activity occurs. Whereas the first group of antibodies inhibits TSH-stimulated function, they do not inhibit the stimulatory antibodies which mimic TSH, an observation consistent with the 2 component hypothesis of the receptor model. The third group of antibodies have a mix of properties from the first two groups and suggests that the TSH receptor in situ is an actual complex of the two components or that there are common carbohydrate determinants in the functional sites of each receptor component. Implications of a TSH receptor structure in which its ganglioside and glycoprotein components are in equilibrium with pools of free components and, in turn, components important for cholera toxin, tetanus toxin and interferon receptors are discussed. In regard to the pathogenesis of Graves' disease, the data indicate that thyroid stimulating autoantibodies are autoimmune equivalents of cholera toxin with respect to the importance of ganglioside function. Since antiidiotype studies of antibodies against TSH confirm a structural relationship between receptors for thyrotropin, cholera toxin, and thyroid stimulating autoantibodies, the data establish an unequivocal role for the ganglioside in TSH receptor structure which facilitates interpretation of in vitro experiments aimed at understanding the mechanism of ganglioside-ligand interactions.
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PMID:Gangliosides, the thyrotropin receptor, and autoimmune thyroid disease. 633 Nov 33

Thyroid hormone exerts profound effects on the activity of the hormone-sensitive adenylate cyclase system in the heart. Distinct guanine nucleotide-binding regulatory proteins (G-proteins) mediate stimulatory and inhibitory influences on adenylate cyclase activity. To examine whether the effects of thyroid hormone on adenylate cyclase involve specific changes in G-protein subunit expression, the influence of tri-iodothyronine (T3) on the biosynthesis and activity of G-proteins in neonatal rat ventricular myocytes was determined. In myocytes challenged with T3 for 5 days, Gs alpha levels increased by 4 +/- 0.5-fold, whereas Gi2 alpha levels declined by more than 80%. T3 down-regulated Gi2 alpha mRNA by 60% within 3 days, but had no effect on Gs alpha mRNA. The basis for the decline in Gi2 alpha mRNA was the T3-mediated suppression of Gi2 alpha gene transcription by 80 +/- 9% within 4 h. The decline in Gi2 alpha mRNA in response to T3 produced a 2-fold decrease in relative rate of synthesis of Gi2 alpha but not in its half-life (46 +/- 7 h). Gs alpha synthesis was not altered by T3, but the half-life of Gs alpha increased from 50 +/- 6 h in control cells to 72 +/- 8 h in T3-treated cells. In addition, T3 provoked the translocation of Gs alpha from the cytoplasmic to the membranous compartment. Membranous Gs alpha increased from 30 +/- 6% to 61 +/- 7% of total cellular Gs alpha, whereas cytoplasmic Gs alpha declined from 68 +/- 6% to 33 +/- 8% within 1 day of exposure to T3. T3-mediated up-regulation of Gs alpha enhanced the activation of myocardial adenylate cyclase by the stimulatory pathway whereas the down-regulation of Gi2 alpha attenuated the deactivation of myocardial adenylate cyclase by the inhibitory pathway.
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PMID:Thyroid hormone regulation of transmembrane signalling in neonatal rat ventricular myocytes by selective alteration of the expression and coupling of G-protein alpha-subunits. 774 15

In MC3T3-E1 mouse osteoblastic cells, the adenylate cyclase activator forskolin increases osteocalcin (OC) mRNA levels. We have analyzed the effects of forskolin and 8-Br cAMP on the transcriptional activity of the rat OC promoter (with luciferase reporter) in MC3T3-E1 cells. Both forskolin and 8-Br cAMP activate the rat OC promoter 2- to 5-fold. By 5' deletion analysis, we have mapped the cAMP response to the region -121 to -92. The 48-base pair rat OC promoter region -121 to -74 (hence denoted ROCRR) can confer cAMP responsiveness to an unresponsive heterologous minimal promoter. Crude nuclear extracts prepared from MC3T3-E1 cells form three complexes with the ROCRR by gel shift analysis. No specific change in nuclear factor binding in response to cellular forskolin treatment could be demonstrated. Intriguingly, two nuclear factor complexes bound to the ROCRR also recognized the thyroid hormone response element palindrome (AGGTCATGACCT) but did not bind the classic cAMP (TGACGTCA) or glucocorticoid (AGAACANNNTGTTCT) response elements. The rat OC promoter possesses two directly repeated PuGGTCA steroid hormone response element hexamer motifs (bottom strand) in the region -114 to -93 within the ROCRR, separated by a 10 nucleotide spacer. Oligos encoding the individual rat OC hexamer sites compete for the ROCRR DNA:protein complexes recognized by the thyroid hormone response element palindrome. Removal of the up-stream hexamer site by 5' deletion (-121 to -100) in the context of the native OC promoter abrogates cAMP responsiveness. Taken together, these data suggest that this novel rat OC cAMP response region assembles a protein:DNA complex containing member(s) of the steroid hormone receptor superfamily. Transcriptional activity, but not DNA binding, is regulated by cAMP.
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PMID:Identification of a rat osteocalcin promoter 3',5'-cyclic adenosine monophosphate response region containing two PuGGTCA steroid hormone receptor binding motifs. 786 63

Thyrotropin (TSH) suppression therapy using thyroid hormone plays an important role in the management of patients thyroidectomized for differentiated thyroid cancer. The rationale for TSH suppression is that differentiated thyroid cancer cells have TSH receptors and show increased adenylate cyclase activity following TSH exposure. L-thyroxine is used for long-term therapy. L-triiodothyronine is preferred when suppressive therapy must be discontinued for radioiodine scan, since its shorter half-life allows more rapid increases of TSH levels. The assessment of TSH suppression is still uncertain. The development of second and third TSH assay generations with progressive improvement in sensitivity has made the TRH test unnecessary and has raised the issue of the TSH level indicative of TSH suppression. In clinical practice TSH values below 0.1 mU/L are considered compatible with appropriate TSH suppression. Serum thyroglobulin is a reliable marker of metastatic disease after total surgical and radioiodine ablation of the thyroid gland and it is useful in the surveillance of patients with differentiated thyroid cancer.
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PMID:[Hormonal therapy in differentiated carcinoma of the thyroid gland]. 788 45

In adulthood, thyroid hormone regulates beta adrenergic responsiveness. We addressed whether similar processes operate in the developing brain, thus playing a role in neurotransmitter control of target cell differentiation. Rats were made hyperthyroid [triiodothyronine (T3)] or hypothyroid [propylthiouracil (PTU)] during the immediate perinatal period, and the development of beta adrenergic signal transduction was evaluated in three brain regions. PTU treatment resulted in an ubiquitous deficit in the number of beta receptor binding sites. Although beta adrenergic stimulation of adenylate cyclase activity was also obtunded by PTU, the effects were much less prominent and were restricted to one region (forebrain); comparison with basal adenylate cyclase and with total enzymatic activity (forskolin stimulation) indicated that the differences in isoproterenol response were at the level of adenylate cyclase expression, rather than in specific receptor coupling. PTU also reduced responsiveness of ornithine decarboxylase (ODC), a key enzyme that couples receptors to differentiation, again, changes in receptor-mediated responsiveness reflected alterations in total enzyme activity, rather than effects on receptor coupling. In contrast, measurements of c-fos, a protooncogene that couples cyclic AMP to induction of ODC, showed increased responses to beta adrenergic or cyclic AMP stimulation in PTU-treated animals. The effect of PTU on c-fos responsiveness occurred in the absence of alterations in basal c-fos expression, a situation different from that seen with adenylate cyclase or ODC. T3 administration had only small effects on any of these variables. The role of thyroid hormones thus involves targeting of beta receptors and receptor-mediated stimulation of nuclear transcription factors (c-fos), as well as basal expression of transduction components in the signalling cascade (adenylate cyclase, ODC). The effects of PTU, contrasted with the failure of T3 to enhance development of beta receptors or their transduction components, suggest that thyroid hormone is obligatory for normal development of this pathway, but that endogenous hormone levels are already optimally permissive.
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PMID:Role of thyroid status in the ontogeny of adrenergic cell signaling in rat brain: beta receptors, adenylate cyclase, ornithine decarboxylase and c-fos protooncogene expression. 796 48

The influence of thyroid hormones on the adrenergic regulation of lipolysis was studied in isolated adipocytes removed from the gluteal region of hyper- and hypothyroid women and compared in adipocytes from euthyroid normal women. Noradrenaline significantly enhanced lipolysis in hyperthyroid patients, whereas noradrenaline inhibited lipolysis in hypothyroid patients compared to that in controls. Moreover, beta-adrenergic sensitivity and responsiveness were 10- and 2-fold increased, respectively, in hyperthyroid patients. In hypothyroid patients, beta-adrenoceptor responsiveness was reduced by 50%, whereas beta-adrenergic sensitivity remained unchanged compared with that in controls. Furthermore, the alpha 2-adrenergic and adenosine-induced antilipolytic effects were similar in all thyroid states. The lowered beta-adrenergic responsiveness seen in hypothyroidism could be mimicked by agents acting at the levels of phosphodiesterase (enprofylline), adenylate cyclase (forskolin) and protein kinase (dibutyryl cAMP). In hyperthyroidism, the increased beta-adrenergic sensitivity and responsiveness were not seen when lipolysis was stimulated at the adenylate cyclase, phosphodiesterase, or protein kinase levels. There was no change in the numbers of adipocyte beta- and alpha 2-adrenoceptors in hypothyroidism. However, the number of beta-adrenergic binding sites was doubled, whereas the fraction and affinities of isoprenaline high affinity sites remained unchanged in hyperthyroidism. Thus, the influence of thyroid hormone on catecholamine-stimulated lipolysis in man acts through different mechanisms when adipocytes are exposed to high or low levels of thyroid hormones. In hyperthyroidism, lipolysis adapts to increasing energy demands through an increase in the beta-adrenoceptor number and, thus, a more effective coupling of the adenylate-cyclase complex. In hypothyroidism, the low lipolytic effect of catecholamines seems to be mainly due to an impairment at the protein kinase level or to the hormone-sensitive lipase itself.
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PMID:Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients. 815 18


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