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ABSTRACT: 3-Iodothyronamine (T(1)AM) is an endogenous thyroid hormone derivative with unknown biosynthetic origins. Structural similarities have led to the hypothesis that T(1)AM is an extrathyroidal metabolite of T(4). This study uses an isotope-labeled T(4) [heavy-T(4) (H-T(4))] that can be distinguished from endogenous T(4) by mass spectrometry, which allows metabolites to be identified based on the presence of this unique isotope signature. Endogenous T(1)AM levels depend upon thyroid status and decrease upon induction of hypothyroidism. However, in hypothyroid mice replaced with H-T(4), the isotope-labeled H-T(3) metabolite is detected, but no isotope-labeled T(1)AM is detected. These data suggest that T(1)AM is not an extrathyroidal metabolite of T(4), yet is produced by a process that requires the same biosynthetic factors necessary for T(4) synthesis.
Endocrinology 09/2012; 153(11):5659-67. · 4.46 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T(1)AM) is an endogenous derivative of thyroxine. Recently there have been numerous reports of analytical methods to quantify endogenous T(1)AM levels, but substantial discrepancies in concentration depending on the method of analysis (LC-MS/MS or immunoassay) suggest endogenous T(1)AM may be covalently modified in vivo. Using information dependent acquisition methods to perform unbiased scans for T(1)AM metabolites following a single IP injection in mice, we have identified O-sulfonate-T(1)AM, N-acetyl-T(1)AM and T(1)AM-glucuronide as conjugates occurring in vivo, as well as the oxidatively deaminated 3-iodothyroacetic acid and non-iodinated thyroacetic acid. 3-iodothyroacetic acid, O-sulfonate-T(1)AM and T(1)AM-glucuronide are present in serum at greater concentrations that unmodified T(1)AM and all metabolites are extensively distributed to tissues. These results suggest covalent modifications of T(1)AM may play a critical role in regulating distribution and biological activity of T(1)AM, and analytical methods to quantify endogenous T(1)AM should be able to account for these metabolites as well.
Journal of chromatography. A 07/2012; 1256:89-97. · 4.19 Impact Factor
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ABSTRACT: The primary purpose of this study was to detect and quantify 3-iodothyronamine (T(1)AM), an endogenous biogenic amine related to thyroid hormone, in human blood.
T(1)AM, total T(3), and total T(4) were assayed in serum by a novel HPLC tandem mass spectrometry assay, which has already been validated in animal investigations, and the results were related to standard clinical and laboratory variables.
The series included one healthy volunteer, 24 patients admitted to a cardiological ward, and 17 ambulatory patients suspected of thyroid disease, who underwent blood sampling at admission for routine diagnostic purposes. Seven patients were affected by type 2 diabetes, and six patients showed echocardiographic evidence of impaired left ventricular function.
No intervention or any patient selection was performed.
serum T(1)AM, total and free T(3) and T(4), routine chemistry, routine hematology, and echocardiographic parameters were measured.
T(1)AM was detected in all samples, and its concentration averaged 0.219 ± 0.012 pmol/ml. The T(1)AM concentration was significantly correlated to total T(4) (r = 0.654, P < 0.001), total T(3) (r = 0.705, P < 0.001), glycated hemoglobin (r = 0.508, P = 0.013), brain natriuretic peptide (r = 0.543, P = 0.016), and γ-glutamyl transpeptidase (r = 0.675, P < 0.001). In diabetic vs. nondiabetic patients T(1)AM concentration was significantly increased (0.232 ± 0.014 vs. 0.203 ± 0.006 pmol/ml, P = 0.044), whereas no significant difference was observed in patients with cardiac dysfunction.
T(1)AM is an endogenous messenger that can be assayed in human blood. Our results are consistent with the hypothesis that circulating T(1)AM is produced from thyroid hormones and encourage further investigations on the potential role of T(1)AM in insulin resistance and heart failure.
The Journal of clinical endocrinology and metabolism 01/2012; 97(1):E69-74. · 6.50 Impact Factor
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ABSTRACT: 3-iodothyronamine (T(1)AM) is an endogenous compound which shares structural and functional features with biogenic amines and is able to interact with a specific class of receptors, designed as trace amine associated receptors. T(1)AM has significant physiological effects in mammals and produces a reversible, dose-dependent negative inotropic and chronotropic effect in heart. The aim of the present study was to investigate if T(1)AM is able to reduce irreversible tissue injury in isolated rat hearts subjected to ischemia and reperfusion, as evaluated by triphenyltetrazolium chloride staining. We observed that T(1)AM reduced infarct size at concentrations (125 nM to 12.5 μM) which did not produce any significant hemodynamic action. The dose-response curve was bell-shaped and peaked at 1.25 μM. T(1)AM-induced cardioprotection was completely reversed by the administration of chelerythrine and glibenclamide, suggesting a protein kinase C and K (ATP) (+) -dependent pathway, while it was not additive to the protection induced by cyclosporine A, suggesting modulation of mitochondrial permeability transition. At cardioprotective concentration, T(1)AM reduced the time needed for cardiac attest during ischemia, but it did not affect sarcoplasmatic reticulum Ca(2+) handling, as demonstrated by unaltered ryanodine receptor binding properties. In conclusion, in isolated rat heart T(1)AM produces a cardioprotective effect which is mediated by a protein kinase C and K (ATP) (+) -dependent pathway and is probably linked to modulation of mitochondrial permeability transition and/or ischemic arrest time.
Cardiovascular Drugs and Therapy 08/2011; 25(4):307-13. · 3.13 Impact Factor
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Thomas S Scanlan
The Journal of clinical endocrinology and metabolism 06/2011; 96(6):1674-6. · 6.50 Impact Factor
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ABSTRACT: Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T3. In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T3 required for UCP1 expression. T3 actions are mediated by thyroid hormone nuclear T3 receptors (TR), TRα and TRβ. Studies in mice suggest that TRβ is required for UCP1 induction, whereas TRα regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T3 vs. specific TRβ1 and TRα1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nm). GC-1 at low doses (0.2-10 nm) was less potent than T3, increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T3, GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The α1- and α2-adrenergic D2 responses increased using high T3 doses. In summary, T3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TRβ1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T3 on TRβ1.
Endocrinology 10/2010; 151(10):5074-83. · 4.46 Impact Factor
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ABSTRACT: 3-iodothyronamine (T1AM) is a novel relative of thyroid hormone, able to interact with specific G protein-coupled receptors, known as trace amine-associated receptors. Significant functional effects are produced by exogenous T1AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T1AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T1AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T1AM was detected in rat serum, at the concentration of 0.3±0.03 pmol/ml, and in all tested organs (heart, liver, kidney, skeletal muscle, stomach, lung, and brain), at concentrations significantly higher than the serum concentration, ranging from 5.6±1.5 pmol/g in lung to 92.9±28.5 pmol/g in liver. T1AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T1AM was observed, and at the steady state total cellular or tissue T1AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T1AM underwent oxidative deamination to 3-iodothyroacetic acid. T1AM deamination was inhibited by iproniazid but not pargyline or semicarbazide, suggesting the involvement of both monoamine oxidase and semicarbazide-sensitive amine oxidase. Thyronamine and thyroacetic acid were not detected in heart. Finally, evidence of T1AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low.
Endocrinology 10/2010; 151(10):5063-73. · 4.46 Impact Factor
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The Journal of clinical endocrinology and metabolism 09/2010; 95(9):4476. · 6.50 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T(1)AM) is an endogenous thyroid hormone derivative with distinct biological effects that are largely opposite those of thyroid hormone. Administration of T(1)AM to rodents results in rapid and profound reduction in body temperature, heart rate, and metabolism. The structural similarities between thyroxine, T(1)AM, and monoamine neurotransmitters suggest an intriguing role for T(1)AM as both a neuromodulator and a hormone-like molecule that may constitute a part of thyroid hormone action. Several recent studies into its molecular mechanisms of action have shown that T(1)AM can target extracellular receptors such as the trace amine-associated receptors and the alpha(2A) adrenergic receptor, modulate the membrane transport of neurotransmitters, and serve as a substrate of specific membrane transport cellular uptake machinery. This review discusses recent T(1)AM studies, focusing on both the observed in vivo effects of T(1)AM administration and its actions at the molecular level.
Molecular BioSystems 08/2010; 6(8):1338-44. · 3.53 Impact Factor
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Donald J Roohk,
Krista A Varady,
Scott M Turner,
Claire L Emson,
Richard W Gelling,
Mahalakshmi Shankaran,
Glen Lindwall,
Lauren E Shipp, Thomas S Scanlan,
Jen-Chywan Wang,
Marc K Hellerstein
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ABSTRACT: Glucocorticoids are widely prescribed to treat autoimmune and inflammatory diseases. Although they are extremely potent, their utility in clinical practice is limited by a variety of adverse side effects. Development of compounds that retain the potent immunomodulating and anti-inflammatory properties of classic glucocorticoids while exhibiting reduced adverse actions is therefore a priority. Using heavy water labeling and mass spectrometry to measure fluxes through multiple glucocorticoid-responsive, disease-relevant target pathways in vivo in mice, we compared the effects of a classic glucocorticoid receptor (GR) ligand, prednisolone, with those of a novel arylpyrazole-based compound, L5 {[1-(4-fluorophenyl)-4a-methyl-5,6,7,8-tetrahydro-4H-benzo[f]indazol-5-yl]-[4-(trifluoromethyl)phenyl]methanol}. We show for the first time that L5 exhibits clearly selective actions on disease-relevant pathways compared with prednisolone. Prednisolone reduced bone collagen synthesis, skin collagen synthesis, muscle protein synthesis, and splenic lymphocyte counts, proliferation, and cell death, whereas L5 had none of those actions. In contrast, L5 was a more rapid and potent inhibitor of hippocampal neurogenesis than prednisolone, and L5 and prednisolone induced insulin resistance equally. Administration of prednisolone or L5 increased expression comparably for one GR-regulated gene involved in protein degradation in skeletal muscle (Murf1) and one GR-regulated gluconeogenic gene in liver (PEPCK). In summary, L5 dissociates the pleiotropic effects of the GR ligand prednisolone in intact animals in ways that neither gene expression nor cell-based models were able to fully capture or predict. Because multiple actions can be measured concurrently in a single animal, this method is a powerful systems approach for characterizing and differentiating the effects of ligands that bind nuclear receptors.
Journal of Pharmacology and Experimental Therapeutics 04/2010; 333(1):281-9. · 3.83 Impact Factor
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Timm Schreiber,
Kathrin Gassmann,
Christine Götz,
Ulrike Hübenthal,
Michaela Moors,
Guido Krause,
Hans F Merk,
Ngoc-Ha Nguyen, Thomas S Scanlan,
Josef Abel,
Christine R Rose,
Ellen Fritsche
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ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are persistent and bioaccumulative flame retardants, which are found in rising concentrations in human tissues. They are of concern for human health because animal studies have shown that they possess the potential to be developmentally neurotoxic.
Because there is little knowledge of the effects of PBDEs on human brain cells, we investigated their toxic potential for human neural development in vitro. Moreover, we studied the involvement of thyroid hormone (TH) disruption in the effects caused by PBDEs.
We used the two PBDE congeners BDE-47 and BDE-99 (0.1-10 microM), which are most prominent in human tissues. As a model of neural development, we employed primary fetal human neural progenitor cells (hNPCs), which are cultured as neurospheres and mimic basic processes of brain development in vitro: proliferation, migration, and differentiation.
PBDEs do not disturb hNPC proliferation but decrease migration distance of hNPCs. Moreover, they cause a reduction of differentiation into neurons and oligodendrocytes. Simultaneous exposure with the TH receptor (THR) agonist triiodothyronine rescues these effects on migration and differentiation, whereas the THR antagonist NH-3 does not exert an additive effect.
PBDEs disturb development of hNPCs in vitro via endocrine disruption of cellular TH signaling at concentrations that might be of relevance for human exposure.
Environmental Health Perspectives 04/2010; 118(4):572-8. · 7.04 Impact Factor
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ABSTRACT: Thyroid hormone transporters are responsible for the cellular uptake of thyroid hormones, which is a prerequisite for their subsequent metabolism and action at nuclear thyroid hormone receptors. A recently discovered thyroid hormone derivative, 3-iodothyronamine (T(1)AM), has distinct biological effects that are opposite those of thyroid hormone. Here we investigate the effects of T(1)AM on thyroid hormone transporters using COS-1 cells transfected with the multispecific organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 1C1, as well as the specific thyroid hormone transporters MCT8 and MCT10, and show that T(1)AM displays differential inhibition of T(3) and T(4) cellular uptake by these transporters. T(1)AM inhibits T(3) and T(4) transport by OATP1A2 with IC(50) values of 0.27 and 2.1 microM, respectively. T(4) transport by OATP1C1, which is thought to play a key role in thyroid hormone transport across the blood-brain barrier, is inhibited by T(1)AM with an IC(50) of 4.8 microM. T(1)AM also inhibits both T(3) and T(4) uptake via MCT8, the most specific thyroid hormone transporter identified to date, with IC(50) values of 95 and 31 microM, respectively. By contrast, T(1)AM has no effect on thyroid hormone transport by OATP1B3 and MCT10. Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T(1)AM may play an important role in modulating thyroid hormone delivery and activity in specific target regions in the central nervous system.
Molecular BioSystems 03/2010; 6(8):1403-10. · 3.53 Impact Factor
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ABSTRACT: Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself. This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here, we show that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T(1/2)<2h) of radiolabeled T(3) vs. T(3) (T(1/2) approximately 5-7h). We cannot discern relationships between this effect and ligand size, activity or affinity for TRbeta. One ligand, GC-24, binds the TR LBC and (weakly) to the TRbeta-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T(3) dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T(3) release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T(3) release and that this effect enhances hormone dissociation.
The Journal of steroid biochemistry and molecular biology 09/2009; 117(4-5):125-31. · 2.66 Impact Factor
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ABSTRACT: Estrogens and selective estrogen receptor (ER) modulators such as tamoxifen are known to increase uterine cell proliferation. Mounting evidence suggests that estrogen signaling is mediated not only by ERalpha and ERbeta nuclear receptors, but also by GPR30 (GPER), a seven transmembrane (7TM) receptor. Here, we report that primary human endometriotic H-38 cells express high levels of GPR30 with no detectable ERalpha or ERbeta. Using a novel tamoxifen analogue, STX, which activates GPR30 but not ERs, significant stimulation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was observed in H-38 cells and in Ishikawa endometrial cancer cells expressing GPR30; a similar effect was observed in JEG3 choriocarcinoma cells. STX treatment also increased cellular pools of phosphatidylinositol (3,4,5) triphosphate, a proposed ligand for the nuclear hormone receptor SF-1 (NR5A1). Consistent with these findings, STX, tamoxifen, and the phytoestrogen genistein were able to increase SF-1 transcription, promote Ishikawa cell proliferation, and induce the SF-1 target gene aromatase in a GPR30-dependent manner. Our findings suggest a novel signaling paradigm that is initiated by estrogen activation of the 7TM receptor GPR30, with signal transduction cascades (PI3K and MAPK) converging on nuclear hormone receptors (SF-1/LRH-1) to modulate their transcriptional output. We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers.
Cancer Research 07/2009; 69(13):5415-23. · 7.86 Impact Factor
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ABSTRACT: The trace amine-associated receptor 1 (TAAR(1)) is an aminergic G protein-coupled receptor (GPCR) potently activated by 3-iodothyronamine (1), an endogenous derivative of thyroid hormone. Structure-activity relationship studies on 1 and related agonists showed that the rat and mouse species of TAAR(1) accommodated structural modifications and functional groups on the ethylamine portion and the biaryl ether moiety of the molecule. However, the two receptors clearly exhibited distinct, species-specific ligand preferences despite being remarkably similar with 93% sequence similarity. In this study, we generated single and double mutants of rat and mouse TAAR(1) to probe the molecular recognition of agonists and the underlying basis for the ligand selectivity of rat and mouse TAAR(1). Key, nonconserved specificity determinant residues in transmembranes helices 4 and 7 within the ligand binding site appear to be the primary source of a number of the observed ligand preferences. Residue 7.39 in transmembrane 7 dictated the preference for a beta-phenyl ring, while residue 4.56 in transmembrane 4 was partially responsible for the lower potency of 1 and tyramine for the mouse receptor. Additionally, 1 and tyramine were found to have the same binding mode in rat TAAR(1) despite structure-activity relationship data suggesting the possibility of each molecule having different binding orientations. These findings provide valuable insights into the critical binding site residues involved in the ligand-receptor interaction that can influence compound selectivity and functional activity of aminergic GPCRs.
ACS Chemical Biology 04/2009; 4(3):209-20. · 6.45 Impact Factor
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ABSTRACT: 3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect. In the isolated rat heart 20-25 microM T(1)AM decreased cardiac contractility, but oxygen consumption and glucose uptake were either unchanged or disproportionately high when compared to mechanical work. In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient. In patch clamped cardiomyocytes sarcolemmal calcium current density was unchanged while current facilitation by membrane depolarization was abolished consistent with reduced sarcoplasmic reticulum (SR) calcium release. In addition, T(1)AM decreased transient outward current (I(to)) and I(K1) background current. SR studies involving 20 microM T(1)AM revealed a significant decrease in ryanodine binding due to reduced B(max), no significant change in the rate constant of calcium-induced calcium release, a significant increase in calcium leak measured under conditions promoting channel closure, and no effect on oxalate-supported calcium uptake. Based on these observations we conclude T(1)AM affects calcium and potassium homeostasis and suggest its negative inotropic action is due to a diminished pool of SR calcium as a result of increased diastolic leak through the ryanodine receptor, while increased action potential duration is accounted for by inhibition of I(to) and I(K1) currents.
Journal of Cellular and Molecular Medicine 03/2009; 13(9B):3082-90. · 4.13 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T(1)AM) and 3,3',5-triiodothyroacetic acid (Triac) are bioactive metabolites of the hormone thyroxine (T(4)). In the present study, the ability of T(1)AM and 3,3',5-triiodothyronamine (T(3)AM) to be metabolized to 3-iodothyroacetic acid (TA(1)) and Triac, respectively, was investigated. Both T(1)AM and T(3)AM were converted to their respective iodinated thyroacetic acid analogues in both cell and tissue extracts. This conversion could be significantly inhibited with the monamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) inhibitor iproniazid. TA(1) was found to be present in trace quantities in human serum and in substantial levels in serum from T(1)AM-treated rats. These results demonstrate that iodothyronamines are substrates for amine oxidases and that this metabolism may be the source of the corresponding endogenous arylacetic acid products Triac and TA(1).
ChemBioChem 01/2009; 10(2):361-5. · 3.94 Impact Factor
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Thomas S Scanlan
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ABSTRACT: 3-Iodothyronamine (T(1)AM) is an endogenous compound with chemical features that are similar to thyroid hormone. T(1)AM has a carbon skeleton identical to that of T(4) and contains a single carbon-iodine bond. Theoretically, T(1)AM could be produced from T(4) by enzymatic decarboxylation and deiodination. Recent studies show that T(1)AM and higher iodinated thyronamines are subject to similar metabolic processing as iodothyronines such as T(4), suggesting a biological linkage between iodothyronines and iodothyronamines. In addition, single doses of T(1)AM administered to rodents induce a hypometabolic state that in certain ways resembles hibernation and is opposite to the effects of excess T(4). This review will discuss the latest developments on this recently discovered thyroid hormone derivative.
Endocrinology 01/2009; 150(3):1108-11. · 4.46 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T(1)AM) is a naturally occurring thyroid hormone metabolite with distinct biological effects that are opposite those of thyroid hormone. The known molecular targets of T(1)AM include both plasma membrane and intracellular proteins, suggesting that intracellular transport of T(1)AM may be an important component of its action, although no uptake mechanism has yet been described. Using various human cell lines, we show that, indeed, cellular uptake of T(1)AM occurs in multiple cell types and that this process involves specific, saturable, and inhibitable transport mechanisms. These mechanisms are sodium and chloride independent, pH dependent, thyronamine specific, and do not involve the likely candidate transporters of other monoamines, organic cations, or thyroid hormones. A large-scale RNA interference screen targeting the entire solute carrier superfamily of transporter genes reveals that the transport of T(1)AM into cells involves multiple transporters, and we identify eight transporters that may contribute to the uptake of T(1)AM in HeLa cells. This type of transporter small interfering RNA screening approach can be used in general to identify the constellation of transporters that participate in the intracellular disposition of compounds.
Endocrinology 01/2009; 150(4):1991-9. · 4.46 Impact Factor
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ABSTRACT: Thyroid hormone (T(3)) influences cell proliferation, death and differentiation during development of the central nervous system (CNS). Hormone action is mediated by T(3) receptors (TR) of which there are two subtypes, TRalpha and TRbeta. Specific roles for TR subtypes in CNS development are poorly understood. We analyzed involvement of TRalpha and TRbeta in neural cell proliferation during metamorphosis of Xenopus laevis. Cell proliferation in the ventricular/subventricular neurogenic zones of the tadpole brain increased dramatically during metamorphosis. This increase was dependent on T(3) until mid-prometamorphosis, after which cell proliferation decreased and became refractory to T(3). Using double labeling fluorescent histochemistry with confocal microscopy we found TRalpha expressed throughout the tadpole brain, with strongest expression in proliferating cells. By contrast, TRbeta was expressed predominantly outside of neurogenic zones. To corroborate the histochemical results we transfected living tadpole brain with a Xenopus TRbeta promoter-EGFP plasmid and found that most EGFP expressing cells were not dividing. Lastly, treatment with the TRalpha selective agonist CO23 increased brain cell proliferation; whereas, treatment with the TRbeta-selective agonists GC1 or GC24 did not. Our findings support the view that T(3) acts to induce cell proliferation in the tadpole brain predominantly, if not exclusively, via TRalpha.
Developmental Biology 12/2008; 326(1):155-68. · 4.07 Impact Factor
