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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was initiated to define the dose- and time-dependence of triiodothyronine (T3) action on Na-K-ATPase in single microdissected nephron segments. For this purpose, the activity and the number of catalytic sites of Na-K-ATPase, as determined by the specific binding of 3H-ouabain, were measured following a single injection of T3 to rabbits thyroidectomized since 8-12 days. Triiodothyronine restored both the activity and the number of catalytic sites of Na-K-ATPase in a dose-dependent manner in all nephron segments where the enzyme was decreased following thyroidectomy, i.e., the proximal and the collecting tubule. At a dose of 50 micrograms/kg bw, T3 restored Na-K-ATPase activity and 3H-ouabain binding with the same kinetics. However, the kinetics depended on the nephron segments: in the proximal tubule, Na-K-ATPase stimulation occurred after a 12 h period of latency and was completed within 24 h whereas in the collecting tubule, the stimulation was biphasic with a first increase within the first 3 h and a second increase concomitantly to that observed in the proximal tubule. These results indicate that thyroid hormones regulate Na-K-ATPase activity by altering the number of catalytic sites of the enzyme. This control depends on two different mechanisms which differ by their time-dependence.
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PMID:Kinetics of triiodothyronine action on Na-K-ATPase in single segments of rabbit nephron. 301 35

Since thyroid hormones and mineralocorticoids were observed to stimulate kidney Na-K-ATPase in similar sites and with similar time courses, this study was initiated to evaluate whether aldosterone is involved in the stimulation of Na-K-ATPase observed in collecting tubules 3 h after triiodothyronine (T3) administration to thyroidectomized (TX) rabbits. Results indicate that: Plasma aldosterone level decreased markedly in TX rabbits but was not restored 3 h after T3 injection; Early stimulation of Na-K-ATPase by T3 was abolished when plasma aldosterone level was suppressed by adrenalectomy or when aldosterone effects were blocked by spironolactone; Administration of aldosterone to TX rabbits mimicked the action of T3; Sensitivity of Na-K-ATPase to aldosterone markedly decreased after thyroidectomy. These results demonstrate an interaction between aldosterone and T3 in the control of Na-K-ATPase in the collecting tubule. Triiodothyronine enhances the sensitivity of Na-K-ATPase to aldosterone which, in turn, produces a stimulatory action despite the decreased plasma level observed during hypothyroidism.
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PMID:Triiodothyronine enhances renal response to aldosterone in the rabbit collecting tubule. 302 30

Since in skeletal muscle circulating L-T3 is the only source for the hormone bound to nuclei, we investigated the intracellular and intranuclear transport of L-T3 in L6E9 rat skeletal muscle cells. The characteristics of this process were assessed by analyzing the nuclear bound L-T3 as a marker of the internalized hormone and by determining the initial rate of L-T3 uptake. [125I]L-T3 cellular uptake at 37 C reached a plateau at 2 h when the nuclear uptake, after an initial lag phase, was still increasing and represented 4.7% of the cellular uptake. Incubation at 4 C caused [125I]L-T3 cellular uptake to decrease by 77% and nuclear uptake to be abolished. A similar effect on [125I]L-T3 nuclear uptake was obtained after myoblasts were incubated at 37 C with a 1000-fold excess of unlabeled L-T3. The addition of various inhibitors of ATP production, cytoskeleton integrity, endocytosis, and Na+, K+-ATPase that did not interfere with [125I]L-T3 binding to the cell surface or to isolated nuclei caused a dose-dependent reduction of both extranuclear and nuclear uptake, ranging from 34-85%. Scatchard analysis revealed the presence on the myoblast surface of L-T3 high affinity (Ka = 1.6 X 10(9) M-1) and low affinity (Ka = 5.4 X 10(6) M-1) binding sites; other iodothyronines exhibited lower affinity for both sites. Kinetic analysis of L-T3 transport after 60-sec incubation at 23 C defined a process with a Km of 17 +/- 5.6 nM and a maximum velocity of 83 +/- 35 pmol/mg DNA. These results indicate the existence in rat myoblasts of a temperature-dependent, energy-requiring, saturable, and stereospecific L-T3 uptake mechanism, probably mediated through an endocytotic pathway, located on the myoblast plasma membrane, that may regulate L-T3 action in skeletal muscle.
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PMID:Intracellular transport of 3,5,3'-triiodo-L-thyronine in rat skeletal myoblasts. 367 43

The relationship between net tubular reabsorption of sodium and renal microsomal sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase) was evaluated in hypothyroid and hyperthyroid rats and in age-matched euthyroid controls. Tubular sodium reabsorption per gram of kidney was lower in thyroidectomized rats than in controls (186+/-14 vs. 246+/-12 mueq/min; P < 0.005) and was accompanied by a quantitatively similar reduction in Na-K-ATPase specific activity (49.4+/-2.4 vs. 65.8+/-2.3 mumol inorganic phosphate (P(t))/mg protein per h; P < 0.001). This decrement was present in both cortex and outer medulla, and was limited to Na-K-ATPase since other representative enzymes not involved in sodium transport (magnesium-dependent adenosine triphosphatase [Mg-ATPase], glucose-6-phosphatase, 5'-nucleotidase) remained unchanged or increased in the hypothyroid animals. Conversely, Na-K-ATPase rose when sodium reabsorption increased in euthyroid rats treated with triiodothyronine. Subsequent experiments were performed to determine to what extent the decrease in Na-K-ATPase is due to lack of thyroid hormone per se or to an adaptive response to decreased reabsorptive sodium load. Triiodothyronine in concentrations of 10(-12) to 10(-5) M had no effect in vitro on microsomal Na-K-ATPase of either thyroidectomized or euthyroid rats. When hypothyroid rats were uninephrectomized or treated with methylprednisolone, sodium reabsorption per gram kidney increased markedly and was similar to that of intact controls. Despite persistence of the hypothyroid state, Na-K-ATPase specific activity also increased to levels not significantly different from euthyroid animals. These data suggest that decreased tubular sodium transport is a major determinant of the reduction in renal Na-K-ATPase in thyroid deficiency since the latter can be reversed by increasing sodium reabsorption during continuing hypothyroidism. Furthermore, the modest sodium leak of hypothyroid animals does not appear to be due to decreased Na-K-ATPase since it was not corrected by uninephrectomy despite restoration of both cortical and medullary Na-K-ATPase activity to normal by this maneuver. The close correlation between net sodium reabsorption and Na-K-ATPase in all the experimental situations described here demonstrates that renal Na-K-ATPase changes adaptively in hyper- or hypothyroidism as it does in numerous situations in the normal animal, in accord with its postulated role in the active transport of sodium across the renal tubule.
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PMID:Renal sodium- and potassium-activated adenosine triphosphatase and sodium reabsorption in the hypothyroid rat. 434 43

Data and arguments are presented that provide evidence of a role played by thyroid hormones (TH) in cell reliability improvement. This role may be determined by synergistic TH action on the following key cell reliability systems: (1) reactive oxygen species (ROS) attack inhibition, and (2) genetic structure repair from injuries inflicted in the course of endogenous and induced mutagenesis. (1) New approaches to ROS oxidation defence were examined. It has been shown that Ca(2+)-ATPase and, probably, regulatory proteins of cell membranes may be the main target for oxidative attack. Protein phosphorylation as well as use of dithiothreitol will lead to a protective action against Ca2+ transport damaging in aorta smooth muscle sarcoplasmic reticulum under oxidation by HOCl, the most toxic ROS of activated neutrophils, whereas thyroxine (T4) and 3,5,3'-triiodothyronine (T3) validly inhibit chemiluminescence in human neutrophils activated by pyrogenal, a lipopolysaccharide from Salmonella typhi cell wall. As this takes place, TH most likely block neutrophil stimulation at the receptor-ligand interaction level. In this case L-T4 and L-T3 antioxidative effect is greater than that of DL-thyroxine and much greater than that produced by such a potent antioxidant as 4-methyl-2,6-diisobutyl phenol. (2) T4 acts as reparogen in rat liver cells under X-ray irradiation when a dose measuring one-half of daily hormone production by the normally functioning thyroid gland is administered to animals. Ionizing radiation dose reduction factor reached 1.3-1.4 following T4 administration. Reparogenic effect of T4 persists for at least 2 months from the moment the hormone has been administered and can be reduced in the presence of dinitrophenol. It is important to note that antioxidant and reparogenic TH potential can manifest itself within the range of physiologic concentrations of these hormones. Therefore, stimulation of cell reliability systems with TH may prove to be important for correcting conditions caused by errors in energy- and Ca(2+)-dependent DNA repair under extensive ROS attack. In particular, taking into account different responsiveness of normal and neoplastic tissues to TH, the use of TH reparogenic as well as antioxidant potential may contribute significantly to the improvement of antitumor radiotherapy efficacy.
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PMID:Thyroid hormones and regulation of cell reliability systems. 794 74

We have analyzed the functional and morphological effects of corticosteroid hormones in a SV40-transformed rabbit cortical-ascending-limb (CAL) cell line (RC.SV2, Vandewalle et al., 1989) having mineralocorticoid (MR) and glucocorticoid (GR) receptors (Rafestin-Oblin et al., 1993). Both aldosterone and dexamethasone (5 x 10(-8) M) induced a marked increase in (3H)ouabain binding (used to quantify membrane Na(+)-K+ ATPase) detectable as early as 6 hours and maximal at 24 hours (+56-57%) (due to a 1.6-1.8-fold increase in cell membrane binding sites without Kd alteration), and significantly augmented the ouabain-sensitive component of Rb+ influx. Triiodothyronine (T3, 10(-9) M) also stimulated ouabain binding by 21% but was not permissive for steroid action, whereas 5 micrograms/ml insulin had no effect. Both steroid hormones, T3 and insulin induced the formation of domes that was tightly correlated with ouabain binding (r = 0.949) except for insulin. The effects of aldosterone and dexamethasone on cell monolayers and cell ultrastructure were, however, strikingly different as aldosterone induced a marked amplification of basolateral areas with appearance of large intercellular spaces, reminiscent of the changes observed in deoxycorticosterone-treated rats, whereas dexamethasone predominantly influenced cell height. This discrepancy might be due to specific occupancy of MR and GR by aldosterone and dexamethasone, respectively, and/or to nongenomic effects of dexamethasone. We have thus characterized a cell culture model making it possible to analyze the actions of mineralocorticoid and glucocorticoid hormones in the mammalian kidney.
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PMID:Phenotypic effects of aldosterone and dexamethasone in a SV40-transformed mammalian cortical ascending limb cell line exhibiting mineralocorticoid receptors. 839 80

Earlier work had shown that JH acts on the membrane of the follicle cell of Locusta migratoria, bringing about a rapid reduction in volume which can be detected in vitro by measuring the increase in optical path difference using quantitative interference microscopy. The juvenoid fenoxycarb, a phenoxyphenyl derivative, is unrelated in structure to the juvenile hormones (which are derivatives of farnesoic acid), but it also caused a reduction in volume of the cells in vitro as measured by an increase in the optical path difference. The vertebrate hormone thyroxine, and thyronine, the non-iodinated derivative of thyroxine, also phenoxy phenyl compounds, evoked a response like fenoxycarb. The effect of thyroxine was abolished by ouabain, which inhibits Na+/K+ ATPase, the effector molecule for JH, and inhibited by ethoxyzolamide which inhibits the binding of JH to a putative membrane receptor. Triiodothyronine, the effective vertebrate hormone, acted at a lower threshold and optimum concentration, and had a greater magnitude of effect than the other compounds tested. These facts suggest that these phenoxyphenyl compounds are JH agonists and that the membrane receptor for JH may resemble a possible membrane receptor for thyroxine.
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PMID:Fenoxycarb and thyroid hormones have JH-like effects on the follicle cells of Locusta migratoria in vitro. 875 10

The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypothyroidism or hyperthyroidism. Triiodothyronine (T3)-induced changes in cardiac function can result from direct or indirect T3 effects. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independently of nuclear T3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. The T3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T3 increases the heart transcription of the myosin heavy chain (MHC) alpha gene and decreases the transcription of the MHC beta gene, leading to an increase of myosin V1 and a decrease in myosin V3 isoenzymes. Myosin V1, which is composed of two MHC alpha, has a higher myosin ATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an increased velocity of contraction. T3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum (SR). This T3 effect results from T3-induced increases in the level of the mRNA coding for the SR calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the SR. Overall, T3 leads to an increase in ATP consumption in the heart. In addition, less chemical energy of ATP is used for contractile purposes and more of it goes toward heat production, which causes a decreased efficiency of the contractile process in the hyperthyroid heart. The pathophysiologic basis for myxedema is the opposite of that discussed for the hyperthyroid heart. In addition to decreased direct effects of thyroid hormone in cardiac myocytes, indirect effects occur through decreases in peripheral oxygen consumption and changes in hemodynamic parameters. Myofibrillar swelling with loss of striation and interstitial fibrosis occurs on histologic examination of hypothyroid hearts. In addition, accumulation of mucopolysaccharide substances (Glycosaminoglycans) can be demonstrated. On electron microscopic examination, mitochondria show disruption and lipid inclusion. Cardiac papillary muscle obtained from animals with hypothyroidism shows a depression of the force velocity curve and reduced rate of tension development, indicating significant contractile abnormalities. In patients with hypothyroidism, a true enhanced incidence of hypertension (increased peripheral vascular resistance) has been found. In addition, hypercholesterolemia and impairment of fatty acid mobilization are associated with myxedema and present additional risk factors for the development of atherosclerotic cardiovascular disease.
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PMID:[Cardiovascular effects of thyroid hormones]. 906 69

Interactions of L-triiodothyronine (T3) in adult rat cerebrocortical synaptosomes were studied in vitro. Scatchard plot analysis revealed two sets of T3 binding sites. The degree of saturation of T3 binding sites (putative receptor) correlated well with the dose-dependent inhibition of Na(+)-K(+)-ATPase activity in synaptosomes. The relative binding affinities and relative inhibition of enzyme activities for different TH analogues were L-T3 > T3-amine > TRIAC = L-T4 > r-T3 > T2 and L-T3 > T3-amine > TRIAC > L-T4 > r-T3 > T2, respectively. The present study demonstrates the nature of inhibition of synaptosomal Na(+)-K(+)-ATPase activity may be as a function of T3 occupancy of synaptosomal receptor sites in adult mammalian brain.
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PMID:Specific binding of L-triiodothyronine modulates Na(+)-K(+)-ATPase activity in adult rat cerebrocortical synaptosomes. 960 84

The thyroid hormone L-T3 elicits either a stimulatory or an inhibitory effect on expression of the Na,K-adenosine triphosphatase alpha3-subunit gene in primary cultures of neonatal rat cardiac myocytes. The present study was undertaken to characterize a negative thyroid hormone response element present within the rat Na,K-adenosine triphosphatase alpha3-subunit gene proximal promoter. Transient transfection assays indicated that the DNA-binding domain of thyroid hormone receptor was essential for mediating repression of alpha3 gene transcription by thyroid hormone. This negative effect of thyroid hormone was enhanced in the presence of cotransfected retinoid X receptor and its ligand 9-cis-retinoic acid. Inhibition of alpha3 chimeric gene expression by thyroid hormone was dependent on the initial cell plating density. The negative thyroid hormone response element was localized to a region between nucleotides -68 to -6 of the alpha3 gene. Electrophoretic mobility shift assays showed that thyroid hormone receptor binds in a synergistic manner as a heterodimer with retinoid X receptor to two sites at positions -62 to -41 and -39 to -17 of the alpha3 gene promoter. The upstream and downstream heterodimer binding sites coexist with CAAT and TATA elements, respectively.
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PMID:Characterization of a negative thyroid hormone response element in the rat sodium, potassium-adenosine triphosphatase alpha3 gene promoter. 968 92


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