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)

The specific role of each subtype of thyroid hormone receptor (TR) on skeletal muscle function is unclear. We have therefore studied kinetics of isometric twitches and tetani as well as fatigue resistance in isolated soleus muscles of R-alpha(1)- or -beta-deficient mice. The results show 20-40% longer contraction and relaxation times of twitches and tetani in soleus muscles from TR-alpha(1)-deficient mice compared with their wild-type controls. TR-beta-deficient mice, which have high thyroid hormone levels, were less fatigue resistant than their wild-type controls, but contraction and relaxation times were not different. Western blot analyses showed a reduced concentration of the fast-type sarcoplasmic reticulum Ca(2+)-ATPase (SERCa1) in TR-alpha(1)-deficient mice, but no changes were observed in TR-beta-deficient mice compared with their respective controls. We conclude that in skeletal muscle, both TR-alpha(1) and TR-beta are required to get a normal thyroid hormone response.
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PMID:Isometric force and endurance in soleus muscle of thyroid hormone receptor-alpha(1)- or -beta-deficient mice. 1071 78

The mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) are members of the steroid/thyroid hormone receptor superfamily of ligand inducible transcription factors and have been shown to bind the glucocorticoid response element (GRE). Sodium-potassium ATPase (Na/KATPase) is a major target of mineralocorticoids. Both aldosterone and glucocorticoids activate the human Na/K ATPase alpha1 subunit and beta1 subunit genes transcriptionally. However, the mechanisms of corticosteroid regulation of mammalian Na/K ATPase subunit gene expression are not known. In this investigation, we report for the first time that cell lines (T-84 and 293) express endogenous MR by RT-PCR message expression. However, the protein product was not expressed as determined by western blot analyses. In transactivation studies of MR with GRE31, we detected MR expression at low concentrations of aldosterone. We also performed Northern blot and nuclear run-off transcription assays to further confirm that the regulation is transcriptional. We conclude that the transcriptional regulation of the human Na/K ATPase alpha1 and beta1 subunits by aldosterone occurs via the involvement of the MR.
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PMID:Transcriptional regulation of the human Na/K ATPase via the human mineralocorticoid receptor. 1071 22

A -1027 bp to + 108 bp region of Na-K-ATPase alpha3 gene promoter has been searched for the presence of thyroid response elements (TRE). Computer analysis of this sequence using a consensus TRE sequence revealed the presence of four putative TRE rich regions referred to as regions I (-636 to -457 bp), II (-218 to -106 bp), III (-106 to -6 bp) and IV (-6 to +108 bp). Cotransfection of the luciferase linked full length construct as well as constructs progressively devoid of the TRE rich regions in Cos1 cells revealed that regions I and III are positively regulated by T3 whereas there are some sequences in region II which can suppress the positive regulatory effect of region III but not of region I. TRE IV seems to have no functional role. EMSA of the three functional TRE rich regions (I, II and III) showed strong and specific interaction with thyroid hormone receptor (TR) cloned and expressed in baculovirus. The overall results suggest the regulation of Na-K-ATPase alpha3 gene by T3 is complex involving several thyroidal regulatory elements.
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PMID:Identification of thyroid regulatory elements in the Na-K-ATPase alpha3 gene promoter. 1171 May 59

Changes in thyroid status markedly influence cardiac contractile and electrical activity. The predominant route by which triiodothyronine (T3) affects cardiac action is by exerting a direct effect in cardiac myocytes through binding to thyroid hormone nuclear receptor isoforms. In addition, T3 modifies cardiac action by alterations in the vascular system and decreases afterload of the left ventricle by subtle modification related to the sympathetic system. The importance of T3 nuclear receptor function has been further demonstrated by studies in null mutant mice in which thyroid hormone receptor-alpha (TRalpha) and thyroid hormone receptor-beta (TRbeta) or both are deleted. In mice with null mutations of the TRalpha, a markedly decreased heart rate and decreased contractile performance occurs in contrast to mice with deletion of TRbeta that have a normal heart rate and a normal contractile performance under baseline conditions. Thyroid hormone influences on heart rate are exerted by specific ion channel proteins in the sinus node of the left atrium. Some of these ion channels, such as the IF channel, the sodium/calcium exchanger protein, the L-type and T-type calcium channel, and the ryanodine channel are targets for thyroid hormone action. The increased contractile performance induced by T3 is largely mediated by increased expression of the calcium adenosine triphosphatase (ATPase) of the sarcoplasmic reticulum and decreased expression of phospholamban and T3 increases the phosphorylation status of phospholamban. The significant influence that is exerted by thyroid hormone signaling system related to contractile and electrical activity in the heart and the molecular basis for these alterations continues to be clarified.
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PMID:Cellular action of thyroid hormone on the heart. 1216 5

Neonatal hypothyroidism impairs structural maturation in the brain and results in diminished electrical activities and energy metabolism. We recently found that glucose utilization (CMR(glc)) is markedly depressed throughout the brain in mice with targeted mutations in thyroid hormone receptor alpha1 (TR alpha 1), but not TR beta. Previous studies had shown that CMR(glc) increases linearly with spike frequency in the afferent pathways to synapse-rich regions in neuropil, but not in neuronal cell bodies. To determine whether the decreased CMR(glc) in mutant TR alpha 1(PV/+) mice reflected lesser synaptic density or reduced functional activity in existing synapses, we stimulated vibrissae unilaterally and measured CMR(glc) bilaterally in four stations of the whisker-to-barrel cortex pathway. Baseline CMR(glc) (unstimulated side) was markedly lower in all four stations in the TR alpha 1(PV/+) mutants than in wild-type controls, even though Northern blot and immunohistochemical examinations showed normal Na(+),K(+)-adenosine triphosphatase expression and neuronal differentiation. Despite the lower baseline CMR(glc), however, vibrissal stimulation evoked percent increases in CMR(glc) in the TR alpha 1(PV/+) mutants that were as great as those in wild-type mice. These results indicate that in the TR alpha 1(PV/+) mutants there it is a reduction in synaptic density that is responsible for the decrease in CMR(glc), but functionality of existing synapses is retained.
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PMID:Functional activation of cerebral metabolism in mice with mutated thyroid hormone nuclear receptors. 1293 86

The NuA4 histone acetyltransferase (HAT) multisubunit complex is responsible for acetylation of histone H4 and H2A N-terminal tails in yeast. Its catalytic component, Esa1, is essential for cell cycle progression, gene-specific regulation and has been implicated in DNA repair. Almost all NuA4 subunits have clear homologues in higher eukaryotes, suggesting that the complex is conserved throughout evolution to metazoans. We demonstrate here that NuA4 complexes are indeed present in human cells. Tip60 and its splice variant Tip60b/PLIP were purified as stable HAT complexes associated with identical polypeptides, with 11 of the 12 proteins being homologs of yeast NuA4 subunits. This indicates a highly conserved subunit composition and the identified human proteins underline the role of NuA4 in the control of mammalian cell proliferation. ING3, a member of the ING family of growth regulators, links NuA4 to p53 function which we confirmed in vivo. Proteins specific to the human NuA4 complexes include ruvB-like helicases and a bromodomain-containing subunit linked to ligand-dependent transcription activation by the thyroid hormone receptor. We also demonstrate that subunits MRG15 and DMAP1 are present in distinct protein complexes harboring histone deacetylase and SWI2-related ATPase activities, respectively. Finally, analogous to yeast, a recombinant trimeric complex formed by Tip60, EPC1, and ING3 is sufficient to reconstitute robust nucleosomal HAT activity in vitro. In conclusion, the NuA4 HAT complex is highly conserved in eukaryotes, in which it plays primary roles in transcription, cellular response to DNA damage, and cell cycle control.
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PMID:Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. 1496 70

The heart is an important target of thyroid hormone actions. Only a limited number of cardiac target genes have been identified, and little is known about their regulation by T(3) (3,3',5-triiodothyronine) and thyroid hormone analogs. We used an oligonucleotide microarray to identify novel cardiac genes regulated by T(3) and two thyroid hormone analogs, 3,5-diidodothyropropionic acid (DITPA) and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid]. DITPA binds with lower affinity than T(3) to thyroid hormone receptor alpha1 and beta1 isoforms, whereas CGS 23425 binds selectively to beta1. Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in medium stripped of thyroid hormone ("hypothyroid" control) or treated with T(3), DITPA, and CGS 23425 at concentrations 5 times their respective K(d) values for 48 h. The arrays were scanned and analyzed using an analysis of variance program. Sixty-four genes were identified that were >1.5 times up- or down-regulated by one of the treatments with P < 0.05. The genes regulated by T(3) and DITPA were nearly identical. Thirteen genes were differentially regulated by CGS 23425. Genes encoding contractile proteins, Ca(2+)-ATPase of sarcoplasmic reticulum and several proteins of mitochondrial oxidative phosphorylation, were up-regulated by T(3) and DITPA but not by CGS 23425. These results indicate that some, but not all, of the actions of thyroid hormone analogs can be explained by differences in gene activation.
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PMID:Regulation of gene expression in cardiomyocytes by thyroid hormone and thyroid hormone analogs 3,5-diiodothyropropionic acid and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid]. 1514 46

Hypothyroid heart displays a phenotype of cardioprotection against ischemia and this study investigated whether administration of dronedarone, an amiodarone-like compound that has been shown to preferentially antagonize thyroid hormone binding to thyroid hormone receptor alpha1 (TRalpha1), results in a similar effect. Dronedarone was given in Wistar rats (90 mg/kg, once daily (od) for 2 weeks) (DRON), while untreated animals served as controls (CONT). Hypothyroidism (HYPO) was induced by propylthiouracil administration. Isolated rat hearts were perfused in Langendorff mode and subjected to 20 minutes of zero-flow global ischemia (I) followed by 45 minutes of reperfusion (R). 3,5,3' Triiodothyronine remained unchanged while body weight and food intake were reduced. alpha-Myosin heavy chain (alpha-MHC) decreased in DRON while beta-myosin heavy chain (beta-MHC) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) expression (SERCA) was similar to CONT. In HYPO, alpha-MHC and SERCA were decreased while beta-MHC was increased. Myocardial glycogen content was increased in both DRON and HYPO. In DRON, resting heart rate and contractility were reduced and ischemic contracture was significantly suppressed while postischemic left ventricular end-diastolic pressure and lactate dehydrogenase release (IU/L min) after I/R were significantly decreased. In conclusion, dronedarone treatment results in cardioprotection by selectively mimicking hypothyroidism. This is accompanied by a reduction in body weight because of the suppression of food intake. TRs might prove novel pharmacologic targets for the treatment of cardiovascular illnesses.
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PMID:Dronedarone administration prevents body weight gain and increases tolerance of the heart to ischemic stress: a possible involvement of thyroid hormone receptor alpha1. 1568 16

Triiodothyronine (T3) is known to play a key role in the function of several tissues/organs via the thyroid hormone receptor isoforms alpha (TRalpha) and beta (TRbeta). We have investigated the effects of GC-24, a novel synthetic TRbeta-selective compound, on skeletal muscle fiber-type determination, cross-sectional area, and gene expression in rat skeletal muscles. For fiber typing, cross sections of soleus and extensor digitorum longus (EDL) muscles were stained for myosin ATPase activity at various pHs. Serum T3, T4, and cholesterol levels were also determined. Analysis of highly T3-responsive genes, viz., myosin heavy chain IIa (MHCIIa) and sarcoendoplasmic reticulum adenosine triphosphatase (SERCA1), was performed by quantitative real-time polymerase chain reaction. Equimolar doses of T3 and GC-24 had a similar cholesterol-lowering effect. T3, but not GC-24, decreased fiber type I and increased fiber type II abundance in soleus and EDL muscles. Conversely, in EDL, both T3 and GC-24 decreased the mean cross-sectional area of type I fibers. MHCIIa gene expression was reduced (approximately 50%) by T3 and unchanged by GC-24. SERCA1 gene expression was strongly induced by T3 (approximately 20-fold) and mildly induced by GC-24 (approximately two-fold). These results show that GC-24 does not significantly alter the composition of skeletal muscle fiber type and further strengthens the putative use of GC compounds as therapeutic agents.
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PMID:Thyroid hormone receptor-beta-selective agonist GC-24 spares skeletal muscle type I to II fiber shift. 1594 69

Maladaptive cardiac hypertrophy results in phenotypic changes in several genes that are thyroid hormone responsive, suggesting that thyroid hormone receptor (TR) function may be altered by cellular kinases, including protein kinase C (PKC) isozymes that are activated in pathological hypertrophy. To investigate the role of PKC signaling in regulating TR function, cultured neonatal rat ventricular myocytes were transduced with adenovirus (Ad) expressing wild-type (wt) or kinase-inactive (dn) PKC alpha or constitutively active (ca) PKC delta and PKC epsilon. Overexpression of wtPKC alpha, but not caPKC delta or caPKC epsilon, induced a 28-fold increase (P < 0.001) in TR alpha1 protein in the nuclear compartment and a smaller increase in the cytosol. Furthermore, TR alpha1 mRNA was increased 55-fold (P < 0.001). This effect of PKC alpha was dependent on its kinase activity because dnPKC alpha was without effect. Phorbol 12-myristate 13-acetate (PMA) induced nuclear translocation of endogenous PKC alpha and Ad-wtPKC alpha concomitantly with an increase in nuclear TR alpha1 protein. In contrast, PMA-induced nuclear translocation of dnPKC alpha resulted in a decrease of TR alpha1. The increase in TR alpha1 protein in Ad-wtPKC alpha-transduced cardiomyocytes was not the result of a reduced rate of protein degradation, nor was the half-life of TR alpha1 mRNA prolonged, suggesting a PKC alpha-mediated effect on TR alpha transcription. Although phosphorylation of ERK1/2 was increased in Ad-wtPKC alpha-transduced cells, inhibition of phospho-ERK did not change TR alpha1 expression. PKC alpha overexpression in cardiomyocytes caused marked repression of triiodothyronine (T3)-responsive genes, alpha-myosin heavy chain, and the sarcoplasmic reticulum calcium-activated adenosinetriphosphatase SERCA2. Treatment with T3 for 4 h resulted in significant reductions of PKC alpha in nuclear and cytosolic compartments, and decreased TR alpha1 mRNA and protein, with normalization of phenotype. These results implicate PKC alpha as a regulator of TR function and suggest that nuclear localization of PKC alpha may control transcription of the TR alpha gene, and consequently, affect cardiac phenotype.
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PMID:Nuclear localization of protein kinase C-alpha induces thyroid hormone receptor-alpha1 expression in the cardiomyocyte. 1615 4


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