The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations

Heuer, Heike; Maier, Michael K.; Iden, Sandra; Mittag, Jens; Friesema, Edith C. H.; Visser, Theo J.; Bauer, Karl

doi:10.1210/en.2004-1179

Cited by 239 publications

(175 citation statements)

References 28 publications

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“…Sensitivity to TH thus depends on the expression of TH transporter molecules. Expression of MCT8 in the mouse brain (9) supported the idea that TH import into neurons may be affected in patients afflicted with the Allan-Herndon-Dudley syndrome. Mice deficient in MCT8 recapitulate the disturbed serum thyroid hormone parameters (10,11) but exhibit only mild neurological abnormalities (12).…”

mentioning

confidence: 65%

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

Kinne

Kleinau

Hoefig

et al. 2010

Journal of Biological Chemistry

105

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Monocarboxylate transporter 8 (MCT8, SLC16A2) is a thyroid hormone (TH) transmembrane transport protein mutated in Allan-Herndon-Dudley syndrome, a severe X-linked psychomotor retardation. The neurological and endocrine phenotypes of patients deficient in MCT8 function underscore the physiological significance of carrier-mediated TH transmembrane transport. MCT8 belongs to the major facilitator superfamily of 12 transmembrane-spanning proteins and mediates energy-independent bidirectional transport of iodothyronines across the plasma membrane. Structural information is lacking for all TH transmembrane transporters. To gain insight into structure-function relations in TH transport, we chose human MCT8 as a paradigm. We systematically performed conventional and liquid chromatography-tandem mass spectrometrybased uptake measurements into MCT8-transfected cells using a large number of compounds structurally related to iodothyronines. We found that human MCT8 is specific for L-iodothyronines and requires at least one iodine atom per aromatic ring. Neither thyronamines, decarboxylated metabolites of iodothyronines, nor triiodothyroacetic acid and tetraiodothyroacetic acid, TH derivatives lacking both chiral center and amino group, are substrates for MCT8. The polyphenolic flavonoids naringenin and F21388, potent competitors for TH binding at transthyretin, did not inhibit T 3 transport, suggesting that MCT8 can discriminate its ligand better than transthyretin. Bioinformatic studies and a first molecular homology model of MCT8 suggested amino acids potentially involved in substrate interaction. Indeed, alanine mutation of either Arg 445 (helix 8) or Asp 498(helix 10) abrogated T 3 transport activity of MCT8, supporting their predicted role in substrate recognition. The MCT8 model allows us to rationalize potential interactions of amino acids including those mutated in patients with Allan-HerndonDudley syndrome.

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mentioning

confidence: 65%

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

Kinne

Kleinau

Hoefig

et al. 2010

Journal of Biological Chemistry

105

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“…MCT8 is thought to mediate the transport of T3 in certain neuronal populations where high MCT8 expression was detected by in situ hybridization (Heuer et al, 2005) as well as by immunohistochemistry (unpubl. observations).…”

Section: Role Of Thyroid Hormone Transportersmentioning

confidence: 99%

Thyroid hormone action during brain development: More questions than answers

Horn

Heuer

2010

Molecular and Cellular Endocrinology

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“…However, brain T3 uptake is probably largely determined by transport across the blood-brain barrier (BBB) and/or the blood-CSF barrier (BCB) and indeed MCT8 is importantly expressed in brain capillaries and in the choroid plexus (7,13). The lack of effect of Mct8 inactivation on brain uptake of T4, which is also a substrate for MCT8, may be explained by assuming that T4 is largely transported across the BBB and BCF by OATP1C1 (7,13).…”

Section: Tissue and Hormone-specific Effects Of Mct8 Inactivationmentioning

confidence: 99%

Tissue-specific effects of mutations in the thyroid hormone transporter MCT8

Kersseboom¹,

Visser

2011

Arq Bras Endocrinol Metab

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T hyroid hormone (TH) is important for the development of different tissues, in particular the brain, as well as for the regulation of the metabolic activities of the tissues and thermogenesis throughout life. Most TH actions are initiated by binding of the active hormone 3,3',5-triiodothyronine (T3) to its nuclear receptor. This induces an alteration in proteins associated with the transcription initiation complex, resulting in the stimulation or suppression of the expression of TH responsive genes.The biological activity of TH is thus determined by the intracellular T3 concentration, which is only indirectly dependent on the function of the thyroid gland which secretes predominantly the prohormone thyroxine (3,3',5,5'-tetraiodothyronine, T4). In many target tissues, T3 availability is regulated in a paracrine manner, where T3 supply to target cells is derived from T4 to T3 conversion in neighbouring cells. Brain and cochlea are examples of tissues with paracrine regulation of TH action. In other tissues, such as the pituitary and brown adipose tissue (BAT), T3 may be produced from T4 directly in its target cells, representing an autocrine mechanism of TH action (Figure 1). In yet other tissues such as the liver and the kidneys, intracellular T3 is in rapid exchange with circulating T3. This could be regarded as an endocrine action of T3, although it is still largely derived from peripheral conversion of T4 even in these same tissues.In contrast to the activation of T4 by enzymatic outer ring deiodination (ORD) to T3, TH is inactivated by inner ring deiodination (IRD), which converts T4 to 3,3',5'-triiodothyronine (reverse T3, rT3) and T3 to 3,3'-diiodothyronine (T2) (1). Three iodothyronine deiodinases (D1-3) are involved in these different deiodination reactions (1). D1 is expressed in liver, kidneys and thyroid and has both ORD and IRD activity. It is thought to contribute importantly to production of serum T3, in particular in eu-and hyperthyroid conditions. D2 has only ORD activity and is expressed in brain, pituitary, BAT, thyroid and skeletal muscle. It is essential for local production of T3 in brain, pituitary and BAT, but the enzyme in thyroid and muscle may also be an important site for production of serum T3 in eu-and hypothyroid subjects. D3 is highly expressed in different fetal tissues, placenta and pregnant uterus, and also in adult brain and skin. It has only IRD activity and thus catalyzes the inactivation of TH. Together with D2, D3 has a crucial role in the region-specific and time-dependent regulation of T3 in the developing brain. The deiodinases are homologous selenoprotein embedded in the membrane of the endoplasmic reticulum or the plasma membrane, such that the active sites are located in the cytoplasm (1).TH metabolism and action are intracellular processes that require transport of iodothyronines across the cell membrane. This does not take place by passive diffusion but requires the involvement of specific transporters (2). A number of multi--specific transporters have been identifi...

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The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations

Cited by 239 publications

References 28 publications

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

Thyroid hormone action during brain development: More questions than answers

Tissue-specific effects of mutations in the thyroid hormone transporter MCT8

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