Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human red cell membrane Ca2+-stimulatable, Mg2+-dependent adenosine triphosphatase (Ca2+-ATPase) activity and its response to thyroid hormone have been studied following exposure of membranes in vitro to specific long-chain fatty acids. Basal enzyme activity (no added thyroid hormone) was significantly decreased by additions of 10(-9)-10(-4) M-stearic (18:0) and oleic (18:1 cis-9) acids. Methyl oleate and elaidic (18:1 trans-9), palmitic (16:0) and lauric (12:0) acids at 10(-6) and 10(-4) M were not inhibitory, nor were arachidonic (20:4) and linolenic (18:3) acids. Myristic acid (14:0) was inhibitory only at 10(-4) M. Thus, chain length of 18 carbon atoms and anionic charge were the principal determinants of inhibitory activity. Introduction of a cis-9 double bond (oleic acid) did not alter the inhibitory activity of the 18-carbon moiety (stearic acid), but the trans-9 elaidic acid did not cause enzyme inhibition. While the predominant effect of fatty acids on erythrocyte Ca2+-ATPase in situ is inhibition of basal activity, elaidic, linoleic (18:2) and palmitoleic (16:1) acids at 10(-6) and 10(-4) M stimulated the enzyme. Methyl elaidate was not stimulatory. These structure-activity relationships differ from those described for fatty acids and purified red cell Ca2+-ATPase reconstituted in liposomes. Thyroid hormone stimulation of Ca2+-ATPase was significantly decreased by stearic and oleic acids (10(-9)-10(-4) M), but also by elaidic, linoleic, palmitoleic and myristic acids. Arachidonic, palmitic and lauric acids were ineffective, as were the methyl esters of oleic and elaidic acids. Thus, inhibition of the iodothyronine effect on Ca2+-ATPase by fatty acids has similar, but not identical, structure-activity relationships to those for basal enzyme activity. To examine mechanisms for these fatty acid effects, we studied the action of oleic and stearic acids on responsiveness of the enzyme to purified calmodulin, the Ca2+-binding activator protein for Ca2+-ATPase. Oleic and stearic acids (10(-9)-10(-4) M) progressively inhibited, but did not abolish, enzyme stimulation by calmodulin (10(-9) M). Double-reciprocal analysis of the effect of oleic acid on calmodulin stimulation indicated noncompetitive inhibition. Addition of calmodulin to membranes in the presence of equimolar oleic acid restored basal enzyme activity. Oleic acid also reduced 125I-calmodulin binding to membranes, but had no effect on the binding of [125I]T4 by ghosts. The mechanism of the decrease by long chain fatty acids of Ca2+-ATPase activity in situ in human red cell ghosts thus is calmodulin-dependent and involves reduction in membrane binding of calmodulin.
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PMID:Action of long-chain fatty acids in vitro on Ca2+-stimulatable, Mg2+-dependent ATPase activity in human red cell membranes. 296 20

The effect of culture conditions, serum supplementation or chemically defined medium and the influence of thyroid hormone were studied on the development of the Na+, K+-adenosine triphosphatase (Na+,K+-ATPase) and on the intracellular content of K+ and Na+ ions in cultures which either were greatly enriched in a neuronal cell type, the cerebellar granule cells, or contained a mixed population of cells (brain reaggregates). Foetal rat brain reaggregates displayed lower Na+,K+-ATPase activity when cultured in chemically defined medium than in the presence of serum. Supplementation of the serum-free medium with thyroid hormone resulted in a rise in the Na+,K+-ATPase activity and [3H]ouabain binding to levels similar to those found in the cultures grown in the serum-containing medium. Thyroid hormone had no significant effect on the Mg2+-ATPase activity and on the intracellular content of Na+ and K+ ions. In the granule cell-enriched cerebellar surface cultures the Na+,K+-ATPase activity was lower when the cells were grown in chemically defined medium compared with the serum-containing medium, and the intracellular Na+ to K+ ratio was higher. Thyroid hormone had no effect on the Na+,K+-ATPase activity, [3H]ouabain binding or Mg2+-ATPase activity. The hormone also failed to influence ATPase activities in cerebellar astrocytes maintained in chemically defined medium. Although thyroid hormone had no effect on the Na+,K+-ATPase activity of cultured cerebellar granule cells, treatment with the hormone resulted in a decrease in the ratio of intracellular Na+ to K+ ion content. The effect of the hormone on the Na+,K+-pump activity in live cells was therefore tested by estimating ouabain-sensitive 86Rb uptake. This was regulated as in other cell types, by the rate of Na+ entry: the Na+-ionophore monensin trebled the rate of 86Rb uptake, which was also increased (+30-100%) by 10% foetal calf serum, the maximal response being obtained by about 20 min exposure to serum. The effect was completely blocked by the Na+/H+ exchange inhibitor amiloride. The factor(s) in the serum responsible for the regulation of the Na+,K+-pump were, however, not the thyroid hormones, which failed to affect 86Rb uptake. On the basis of comparing thyroid hormone effects on the different cultures studied it was concluded that not every type of neural cell is target of the hormone action during development.
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PMID:Effect of thyroid hormone and serum on the development of Na+, K+-adenosine triphosphatase and associated ion fluxes in cultures from rat brain. 298 59

Thyroid hormone is known to modulate cell membrane sodium/potassium adenosine triphosphatase (Na/K-ATPase). To determine whether the activity of this enzyme differed in patients with nonthyroidal illness with low levels of circulating thyroid hormones and patients with documented clinical hypothyroidism, we measured Na/K-ATPase activity in red blood cells from patients with hypo- and hyperthyroidism, patients with nonthyroid disease with and without reduced circulating levels of thyroid hormone, and normal subjects. We also assessed whether the activity of this enzyme reflects decreased thyroid hormone action at the cellular level in patients with nonthyroidal illness. Hyperthyroidism was associated with decreased and hypothyroidism with increased erythrocyte Na/K-ATPase activity [142 +/- 24 (+/- SE) and 371 +/- 37 nmol Pi/mg X h; P less than 0.05 and P less than 0.01 compared to normal]. Enzyme activity in cells from patients with nonthyroidal illness and low levels of circulating T3 was significantly higher than that in cells from normal subjects (289 +/- 11 vs. 223 +/- 16 nmol Pi/mg X h; P less than 0.01), but was not significantly different from that in cells from hypothyroid patients. Red cell Na/K-ATPase activity in patients with nonthyroidal illness and normal thyroid function tests (185 +/- 38 nmol Pi/mg X h was indistinguishable from normal values. These data confirm that hyperthyroid patients have decreased red cell Na/K-ATPase activity and provide direct evidence that erythrocyte ATPase activity is increased in hypothyroid patients. The change in enzyme activity in patients with nonthyroidal illness and decreased circulating T3 levels was comparable to that in hypothyroidism. These results suggest that since red cell Na/K-ATPase activity does not distinguish between ill patients with low thyroid function tests and those with hypothyroidism, tissue hypothyroidism may exist in the former group of patients.
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PMID:Erythrocyte sodium/potassium adenosine triphosphatase in thyroid disease and nonthyroidal illness. 298 90

The authors have examined the enzyme histochemical staining of surgically removed human thyroid tissue in an attempt to identify markers that might be useful in the histopathologic diagnosis of thyroid neoplasms. Fresh thyroid glands and other tissues were fixed in cold (4 degrees C) 4% paraformaldehyde and embedded in glycol methacrylate. Forty-two specimens were studied in thin sections, which gave excellent histologic detail and enzyme preservation. Cytologic detail was similar to that in Papanicolaou-stained smears, with good definition of nuclear inclusions and grooves, particularly in cases of papillary carcinoma. The enzyme histochemical reactions studied were as follows: adenosine triphosphatase, alkaline and acid phosphatases, alpha-naphthyl acetate esterase, and 5'-nucleotidase. Thyroid epithelial cells and the benign neoplasms derived from them were typically positive for 5'-nucleotidase, alpha-naphthyl acetate esterase, and acid phosphatase, and negative for adenosine triphosphatase and alkaline phosphatase. Staining for adenosine triphosphatase was present in papillary and follicular carcinomas and was seen in benign glands only under certain circumstances such as Graves' disease. The adenosine triphosphatase reaction therefore appears to be helpful in distinguishing between benign and malignant neoplasms derived from thyroid epithelium in humans and may be a useful adjunct to routine morphology.
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PMID:Enzyme histochemistry and thyroid neoplasia. 301 Jun 99

Thyroid status was altered by use of a low-iodine-perchlorate (PC) regimen and either reversal with NaI or injections of L-3,5,3'-triiodothyronine (T3). The PC regimen decreased renal and hepatic oxygen consumption (QO2), alpha-glycerophosphate dehydrogenase (alpha-GPDH), and Na+-K+-dependent adenosine triphosphatase (Na-K-ATPase) to comparable extents (25 vs. 23%, 26 vs. 39%, and 41 vs. 51%, respectively). Administration of T3 to hypothyroid rats elicited dose-dependent increases in hepatic and renal cortical QO2, ouabain-sensitive oxygen consumption (QO2(t)), alpha-GPDH, and Na-K-ATPase activities. The half-maximal increases in all of the response parameters in both kidney and liver were obtained at dosages of 6-32 micrograms T3/100 g body wt. The equivalences in the renal cortical vs. hepatic responses were indicated by correlation coefficients of approximately 0.97. Kidney and liver nuclei also showed similar high-affinity binding of 125I-T3-K1/2 = 29 vs. 18 micrograms T3/100 g body wt, and Nmax = 1.8 vs. 2.1 ng T3/mg DNA. The patterns of the responses plotted as a function of T3 occupancy of the high-affinity nuclear binding sites were indistinguishable in kidney and liver. These results imply similar modes of action of T3, probably initiated at the nuclear level, in both kidney and liver.
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PMID:Nuclear binding of T3 and effects of QO2, Na-K-ATPase, and alpha-GPDH in liver and kidney. 625 44

The concept of a hypermetabolic state to explain metabolic tolerance to ethanol grew from the recognition that the rate of alcohol metabolism is, in general, limited by the rate at which mitochondria can reoxidize reducing equivalents and thus by the rate at which oxygen can be consumed by the liver. This relationship appears to be most important in conditions in which the alcohol dehydrogenase (ADH)/QO2 ratio is high and is not in conflict with observations suggesting that ADH can, under certain conditions, constitute a rate-determining step for ethanol metabolism in rodents. Liver preparations from animals fed alcohol chronically, in which an increase in ethanol metabolism is shown, consume oxygen at higher rates. This effect, concerning which there is discrepancy among investigators, depends on the type of preparation. Thyroid hormones play a permissive role in the development of the hypermetabolic state, while increased circulating levels of these hormones are not required. Antithyroid drugs inhibit both metabolic tolerance in vivo and the hypermetabolic state. While the hypermetabolic state requires an increased ATP utilization in the form of an adenosine triphosphatase, or an inhibition of ATP synthesis, the different mechanisms proposed for such an effect do not quantitatively account for the increases in oxygen consumption. In humans and animals chronically exposed to ethanol, but withdrawn, oxygen tensions in blood leaving the liver are significantly reduced. In some situations, low oxygen tensions in zone 3 of the hepatic acinus can reach critical hypoxic levels and may lead to cell necrosis. Studies in which the effectiveness of propylthiouracil is tested in human alcoholic hepatitis are discussed.
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PMID:Hypermetabolic state and hypoxic liver damage. 632 88

Thyroid hormone (T3) increases the transcription of the sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) gene (SERCA 2) through three thyroid hormone response elements. The existence of repetitive cis elements with different configurations is likely to serve specific functions such as interactions with nuclear transcription factors. In addition, the presence of different T3 receptor isoforms (T3Rs) may contribute to another level of complexity in providing specificity for T3 action. In this study, we investigated T3R alpha 1-vs. T3R beta 1-specific interactions with the myocyte enhancer-specific factor-2 (MEF-2) on the expression of the SERCA 2 gene in transient transfection assays in embryonal heart-derived H9c2 cells. MEF-2a in combination with either T3R alpha 1 or T3R beta 1 isoforms resulted in a 2.5-fold increase in SERCA 2 transgene expression in the absence of T3. Addition of T3 did not induce any further increase in SERCA 2 expression when T3R alpha 1 and MEF-2a expression vectors were cotransfected. In contrast, in the presence of T3R beta 1 and MEF-2, the addition of T3 increased chlorampenicol acetyltransferase activity by an additional 2.2-fold to a total 5.5-fold increase. The interaction between MEF-2a and T3R is transcription factor specific because another factor that binds to MEF-2 consensus sites (heart factor 1b) was not able to interact with T3R. In addition, MEF-2a failed to interact with other nuclear factors (cAMP response element-binding protein and Egr-1) that stimulate SERCA 2 gene transcription. In addition, we found that a single homologous thyroid hormone response element is not able to mediate the interactions between MEF-2a and T3Rs to increase SERCA 2 gene transcription. Our findings point to T3R isoform-specific interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression.
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PMID:Transcription of the rat sarcoplasmic reticulum Ca2+ adenosine triphosphatase gene is increased by 3,5,3'-triiodothyronine receptor isoform-specific interactions with the myocyte-specific enhancer factor-2a. 897 81

Lithium is used in the prophylaxis of bipolar depressive disorder in augmentation treatment of depression and in the therapy of some cases of unipolar depression. Lithium affects cell function via its inhibitory action on adenosine triphosphatase (ATPase) activity, cyclic adenosine monophosphate (cAMP), and intracellular enzymes. The inhibitory effect of lithium on inositol phospholipid metabolism affects signal transduction and may account for part of the action of the cation in manic depression. Lithium also alters the in vitro response of cultured cells to thyrotropin-releasing hormone (TRH) and can stimulate DNA synthesis. Lithium is concentrated by the thyroid and inhibits thyroidal iodine uptake. It also inhibits iodotyrosine coupling, alters thyroglobulin structure, and inhibits thyroid hormone secretion. The latter effect is critical to the development of hypothyroidism and goiter. Effects on brain deiodinase enzymes and alterations in thyroid hormone receptor concentration in the hypothalamus are under investigation in relation to the therapeutic effect of lithium. The ion affects many aspects of cellular and humoral immunity in vitro and in vivo. This accounts for a rise in antithyroid antibody titer in patients having these antibodies before lithium administration whereas there is no induction of thyroid antibody synthesis de novo. Goiter, due to increased thyrotropin (TSH) after inhibition of thyroid hormone release, occurs at various reported incidence rates from 0%-60% and is smooth and nontender. Subclinical and clinical hypothyroidism due to lithium is usually associated with circulating anti-thyroid peroxidase (TPO) antibodies but may occur in their absence. Iodine exposure, dietary goitrogens, and immunogenetic background may all contribute to the occurrence of goiter and hypothyroidism during long-term lithium therapy. It is currently unclear whether the reported association of lithium therapy and hyperthyroidism are causal, although there is suggestive epidemiological evidence. Finally, lithium therapy is associated with exaggerated response of both TSH and prolactin to TRH in 50%-100% of patients, although basal levels are not usually high. It is probable that the hypothalamic pituitary axis adjusts to a new setting in patients receiving lithium.
Thyroid 1998 Oct
PMID:The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. 982 58

Hypothermic hyperkalemic circulatory arrest has been widely used for myocardial protection during heart surgery. Recent data showed that administration of triiodo-L-thyronine (T3) postoperatively enhanced ventricular function. The effect of hyperkalemic arrest in conjunction with thyroid hormone on the plasma membrane enzyme sodium/potassium-adenosine triphosphatase (Na/K-ATPase), was determined in cultured neonatal rat atrial and ventricular myocytes. Exposure of ventricular myocytes to hyperkalemic medium (50 mM KCl) in the absence of T3 increased expression of the Na/K-ATPase catalytic subunit mRNAs, alpha1 and alpha3 isoforms, by 1.9- and 1.5-fold, respectively (p<0.01), which were accompanied by similar increases (1.4- and 1.8-fold) in protein content. Addition of T3 to the hyperkalemic cultures attenuated these increases in Na/K-ATPase mRNA isoforms to levels of expression observed in cells treated with T3 (10(-8) M) alone. Similarly, expression of the alpha1 mRNA isoform in atrial myocytes was increased (p<0.05) by hyperkalemic conditions, and T3 treatment attenuated this effect. In contrast, although expression of the Na/K-ATPase beta1 mRNA in both atrial and ventricular myocytes was significantly increased by hyperkalemia, addition of T3 did not prevent the hyperkalemic response, and in atrial myocytes T3 significantly increased beta1 mRNA expression 1.8-fold. These results show that expression of cardiac Na/K-ATPase is regulated by T3 and hyperkalemia in an isoform and chamber specific manner, and suggest that use of hyperkalemic cardioplegia during heart surgery may alter plasma membrane ion function.
Thyroid 1999 Jan
PMID:Regulation of Na/K-ATPase gene expression by thyroid hormone and hyperkalemia in the heart. 1003 77

Thyroid hormone exerts predictable effects on the contractile performance of the heart in part by regulating the transcription of genes encoding specific calcium transporter proteins. In a rat model of hypothyroidism, left ventricular (LV) contractile function as measured by ejection fraction was decreased by 22% (P < 0.05), and this was returned to control values with T3 treatment. In confirmation of prior studies, LV phospholamban (PLB) protein content was significantly decreased by 25% and 40% compared with hypothyroid LV when the animals were treated with T3 at two doses, 2.5 and 7.0 microg/day, respectively. The ratio of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2) to PLB protein content was thus increased by 171% and 207%, respectively (P < 0.01). Resolution of the phosphorylated PLB pentamers by SDS-PAGE showed that T3 infusion at 2.5 and 7.0 microg/day decreased (P < 0.001) the amount nonphosphorylated pentamers by 82% and 95%, respectively, in a dose-dependent manner. T3 treatment produced an increase in the proportion of highly phosphorylated PLB pentamers (more than five phosphates) when expressed as a fraction of total pentameric molecules (P < 0.05). Site-specific antibodies showed that the T3-induced increase in phosphorylated PLB pentamers was the result of an increase in both serine 16 and threonine 17 phosphorylation. We conclude that thyroid hormone, in addition to regulating the expression of cardiac PLB, is able to alter the degree of PLB phosphorylation, which correlates with enhancement of LV contractile function. These studies suggest that T3 may augment myocyte calcium cycling via changes in both cAMP- and calcium/calmodulin-dependent protein kinase activities.
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PMID:Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. 1083 Mar 1


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