The plasma membrane and thyroid hormone entry into cells

doi:10.1016/1043-2760(89)90009-X

Trends in Endocrinology & Metabolism

Volume 1, Issue 2, November–December 1989, Pages 90-94

https://doi.org/10.1016/1043-2760(89)90009-X Get rights and content

Abstract

A growing body of evidence indicates that many cells accumulate thyroid hormone by energy-dependent receptor-mediated pathways. Their contributions to the regulation of thyroid hormone metabolism and action are now being addressed.

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Tetraiodothyroacetic acid-conjugated polyethylenimine for integrin receptor mediated delivery of the plasmid encoding IL-12 gene
2017, Colloids and Surfaces B: Biointerfaces
Citation Excerpt :
Therefore, targeting tumor sites using the integrin receptors might be a useful strategy to direct the molecules into the target malignant cells and overcome the barriers limiting the wide clinical application of chemotherapeutics as well as oligonucleotides [15,16]. Previously, it was believed that the entrance of thyroid hormone (l-thyroxine, T4) into the cells occurs via simple diffusion in which the hormone crosses the membrane as a result of the difference between the concentration inside and outside the plasma membrane [17,18]. Interestingly, it has been recently shown that there is a recognition site for thyroid hormone on the integrin receptor which is located at or near the RGD (Arginine-Glycine-Aspartic acid) binding site [7,19].
Targeted delivery by polymer-based nanoparticles has been considered as an efficient approach to transfer genetic materials into cells. Considering the over expression of integrin α_Vβ₃ receptor on tumor cells and the presence of the binding site for tetraiodothyroacetic acid (tetrac) on integrin receptor, we hypothesized that the conjugation of tetrac to polyethylenimine (PEI) might be an effective strategy for pDNA delivery into the cells over-expressing integrins on their surfaces. In order to test the hypothesis, tetrac conjugated PEI/plasmid DNA complexes were prepared and their ability in the delivery of plasmid encoding IL-12 gene was investigated. Moreover, the conjugates were characterized with respect to plasmid DNA condensation ability, particle size and zeta potential as well as cell-induced toxicity and plasmid protection against DNase degradation. The results demonstrated that tetrac conjugated derivatives of PEI were able to condense the plasmid and protect it against enzyme degradation. The results of dynamic light scattering (DLS) and atomic force microscopy (AFM) revealed that the formed nanoparticles were in the size range of 85–125 nm. The highest level of IL-12 gene expression was achieved by terac-conjugated PEIs at the carrier to plasmid ratio of 8 where they could increase the level of gene expression up to 4 fold in the cell lines over-expressing integrin α_Vβ₃ receptor whereas no increase in the level of IL-12 expression in the cell lines lacking integrin receptors was observed. Also, the results of the competitive inhibition of the receptors demonstrated the specificity of transfection for the cells over expressing α_vβ₃ receptor. On the other hand, tetrac conjugation of PEI significantly reduced the polymer-induced apoptotic effects. The results obtained in this investigation suggest the potential of tetrac as a small molecule mimicking the binding properties of integrin binding peptides (e.g., RGD) for targeted gene delivery.
Demonstration of potent lipid-lowering activity by a thyromimetic agent devoid of cardiovascular and thermogenic effects
1996, Atherosclerosis
A potent lipid-lowering thyromimetic (CGS 26214) devoid of cardiac and thermogenic activity was identified based on its ability to preferentially access and bind the nuclear fraction of hepatocytes over that of myocytes in culture. The difference in access achieved with CGS 26214 was at least 100-fold better for hepatocytes than for myocytes. This in vitro hepatoselectivity resulted in a compound with unprecedented in vivo lipid-lowering potency with a minimal effective dose of 1 μg/kg in rats and dogs (~25x that of L-T₃). At the same time, CGS 26214 was free of any cardiovascular effects up to the highest dose tested of 25 mg/kg and 100 μg/kg in rats and dogs, respectively.
Kinetics of internalization and subcellular binding sites for T<inf>3</inf> in mouse liver
1996, Biology of the Cell
The intracellular fate of radiolabeled T₃ taken up by mice hepatocytes in vivo was determined at specific time intervals (2–120 min) after injection by quantitative electron microscopic radioautography. Injection of a 200-fold excess of unlabeled T₃ together with [¹²⁵I]-T₃ resulted in a more than 90% inhibition of radioactivity detected in hepatocytes. A simple grain density (GD) analysis of radioautograms revealed that a specific labeling (GD > 1) was displayed by only five cell compartments: the plasma membrane, lipid droplets, mitochondria, nuclear envelope and nuclear matrix whereas other compartments were not labeled. Labeled compartments showed distinct changes in the pattern of labeling over time: the plasma membrane was labeled only 2 min after T₃ injection, whereas labeling of the nuclear envelope was high at 2 min, decreased at 15 min and progressively increased to maximal measured levels at 120 min. After a lag time of 30 min, nuclear matrix labeling increased progressively with time. Mitochondrial labeling was found to be specific at any time point studied but showed no change over time. These ultrastructural data have been confirmed in vitro by the interaction of T₃ with plasma membrane, nuclear membrane, nuclear matrix and mitochondria by real-time biospecific interaction analysis in a BIAcore^™ system. These results demonstrate that T₃ binds to hepatocytes before internalization, is transported both to mitochondria and to the nuclear envelope and translocated into the nuclear matrix.
Characterization of cell polarity and epithelial junctions in the choriocarcinoma cell line, JAR
1995, Placenta
In the placenta the trophoblast cell layer separates maternal and fetal circulations and is involved in the active transport of selected substances across this barrier. We have used the JAR choriocarcinoma cell line to study aspects of trophoblast membrane transport. To determine whether JAR cells could be used in studies of vectorial transepithelial transport it was necessary to determine whether these cells were polarized and assembled tight junctions. In the present study we investigated JAR cells using a range of markers for specific cell surface domains combined with confocal laser scanning microscopy. Freshly isolated cells initially formed a confluent epithelial monolayer with recruitment of a tight junction-associated protein, ZO-1, and a cell adhesion molecule, E-cadherin, to the surface at sites of cell-cell contact. They did not, however, display cell surface polarization, as NaK-ATPase was not segregated in the basolateral domain, and a differentiated apical cell surface was not assembled. The monolayer stage was also unstable, as continued proliferation resulted in the formation of multilayered aggregates where ZO-1 and E-cadherin were lost from the cell surface. These results suggest that the JAR cell line is unlikely to be a suitable model for studies of transepithelial transport in the placenta.
Characterization of 3,5,3'-triiodo-L-thyronine transport into hepatocytes isolated from juvenile rainbow trout (Oncorhynchus mykiss), and comparison with L-thyroxine transport
1994, General and Comparative Endocrinology
Uptake of 3,5,3′-triiodo-L-thyronine (T₃) by isolated trout hepatocytes was characterized after 40 sec incubation of cells in a balanced salts medium containing [¹²⁵]T₃, and compared to L-thyroxine (T₄) uptake (Riley and Eales, Gen. Comp. Endocrinol. 90, 31-42, 1993). T₃ uptake resembled T₄ uptake in several ways. There was a small (<10%) diffusion component. The balance of the uptake was temperature- and energy-dependent and involved protein carrier, but did not depend on the presence of Na⁺ in the medium or Na⁺transport. Tyrosine and phenylalanine were ineffective competitors. Inhibition by cholchicine and chloroquine indicated an endocytotic process. T₃ uptake differed from T₄ uptake in having a higher pH optimum (6-8) than T₄ (5-6), and in having a much lower K_t (0.074 μM) than T₄ (0.52 μM). T₃ uptake was far more strongly inhibited than T₄ uptake by TRIPROP (8% of control uptake), reverse T₃ (9%), and 3,3′-diiodo-L-thyronine (9%). T₄ inhibited T₃ transport (K_i = 0.18 μM), but kinetic analyses indicated that the mutual inhibitions were noncompetitive, suggesting separate T₃ and T₄ binding sites. In conclusion, T₃ uptake into isolated trout hepatocytes resembles that for T₄ uptake in being an energy-dependent, carrier-mediated endocytotic process, but differs from T₄ uptake in having a lower K_t , a higher pH optimum, and a greater sensitivity to inhibition by related iodothyronines. T₃ and T₄ uptakes may involve separate carrier systems, providing scope for individual control of T₃ and T₄ uptake by trout hepatocytes.
Interactions between transport of triiodothyronine and tryptophan in JAR cells
1994, Molecular and Cellular Endocrinology
We studied the effect of a number of amino acids on uptake of l-triiodothyronine (T₃) in the human choriocarcinoma cell line, JAR. Tryptophan inhibited saturable T₃ uptake by about 57% without any significant effect on the non-saturable uptake. Michaelis constant (K_m) for T₃ uptake was 1.06 ± 0.15 μM (n = 15) with the corresponding maximum velocity (V_max) of 24.2 ± 3.1 pmol/min/mg cellular protein. For tryptophan uptake the K_m was 1.31 ± 0.26 μM (n = 7) and V_maxpmol/min/mg protein. The kinetic parameters for both uptake processes were similar to those reported in normal placenta. Uptake of T₃ was inhibited by tryptophan but not phenylalanine, but tryptophan uptake was inhibited both by T₃ and phenylalanine. Inhibition of T₃ uptake by tryptophan was dose dependent, with an inhibition constant (K_i) of 2.9 ± 0.5 mM. Similarly, tryptophan uptake was inhibited by T₃ and phenylalanine in a dose dependent way with K_i values of 4.9 ± 0.5 μM a 15.6 ± 4.8 μM respectively. K_m for T₃ uptake was significantly increased to 1.86 ± 0.42 μM (n = 4) in the prese unlabelled tryptophan and, similarly, K_m for tryptophan uptake was significantly increased to 9.91 ± 2.57 μM (n = 3) in the presence of 5 μM unlabelled T₃. Efflux of T₃ was progressively inhibited by increasing concentrations of both ligands i.e. was saturable. We conclude that there is mutual competitive inhibition between uptake systems for T₃ and tryptophan in JAR cells, but the kinetic parameters of cross-inhibition of uptake by the substrates suggest that the carriers are distinct. T₃ may be transported in JAR cells by at least two transport systems with differing substrate specificities. We also demonstrated the presence of a saturable membrane carrier mediating the efflux of T₃ from the cells which was subject to trans-inhibition by T₃ and tryptophan.

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Trends in Endocrinology & Metabolism

Brief reviewThe plasma membrane and thyroid hormone entry into cells

Abstract

J Biol Chem

FEBS Lett

Mol Cell Endocrinol

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

FEBS Lett

FEBS Lett

Biochem Biophys Acta

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Nature of thyroid hormone receptors. Translocation of thyroid hormones across plasma membrane

Biokhimya

Binding of thyroid hormones to human plasma lipoproteins

J Clin Endocrinol Metab

Low density lipoproteins enhances T4 uptake by LDL-receptor competent human fibroblasts

T4 entry in normal human fibroblasts is selectively enhanced by low density lipoproteins (LDL)

Carriermediated [125I]T3 uptake by mouse thymocytes

Endocrinology

Role of sodium in thyroid hormone uptake by rat skeletal muscle

J Clin Invest

Characterization of binding and uptake of 3,3′,5-triiodo-i.-thyronine in cultured mouse fibroblasts

Endocrinology

Structural similarities in the plasma membrane 3,3′,5-triiodo-l thyronine receptors from human, rat and mouse cultured cells. Analysis by affinity labeling

Endocrinology

Purification and characterization of a membrane-associated 3,3′,5-triiodo-l-thyronine binding protein from a human carcinoma cell line

Receptor-mediated uptake of 3,3′,-5-triiodo-l-thyronine by cultured fibroblasts

Monoclonal antibodies (MAb) inhibit thyroid hormone (TH) transport into rat liver cells

Ann Endocrinol

Binding of thyroxine-transthyretin complexes to specific cell surface receptors

Clin Res

Active transport of iodothyronines into human cultured fibroblasts

J Clin Endocrinol Metab

Inhibition of uptake of thyroid hormone into rat hepatocytes by preincubation with N-bromoacetyl-3,3′,5-triiodothyronine

Endocrinology

Uptake of L-triiodothyronine by isolated rat liver cells

Biochem J

Plasma protein mediated transport of steroid and thyroid hormones: a critique

Am J Physiol

The influence of extracellular thyroxine binding protein upon the accumulation of thyroxine by tissue slices

J Clin Invest

Cellular uptake of 3,5,3′-triiodothyronine and thyroxine by red blood and thymus cells

Endocrinology

Brief review
The plasma membrane and thyroid hormone entry into cells

Low density lipoproteins enhances T₄ uptake by LDL-receptor competent human fibroblasts

T₄ entry in normal human fibroblasts is selectively enhanced by low density lipoproteins (LDL)

Carriermediated [¹²⁵I]T₃ uptake by mouse thymocytes