Since 2000, a number of thyroid hormone transporters have been identified at the molecular level. These include the Na- taurocholate cotransporting polypeptide (NTCP), different members of the organic anion transporting polypeptide (OATP) family, the L- type amino acid transporters (LATs), members of the monocarboxylate transporter (MCT; SLC16) family and SLC17A4.

Of these transporters, only NTCP (SLC10A1) transports its ligands in a Na+- dependent manner. It is exclusively expressed in liver and transports primarily bile acids. Human NTCP consists of 349 amino acids and has seven transmembrane domains. The NTCP gene is located on chromosome 14q24.1 and has five exons. There are no other thyroid hormone transporters in the SLC10 family. NTCP shows a preference for sulphated over non- sulphated iodothyronines.

Different human OATP members have been shown to transport iodothyronine derivatives. In general, they are multispecific, transporting a variety of ligands. OATPs are glycoproteins containing around 700 amino acids and 12 transmembrane domains. The human OATP1 subfamily contains four members (OATP1A2, 1B1, 1B3, 1C1) with interesting properties. They are encoded by a gene cluster on chromosome 12p12 containing 14– 15 exons. OATP1B1 and 1B3 are expressed only in liver and show preference for sulphated over non- sulphated iodothyronines as ligands. T he latter also holds for OATP1A2, which is expressed in different tissues. OATP1C1 is an exceptional transporter in this subfamily, showing a high preference for T4 as the ligand and almost exclusive expression in the brain, especially in choroid plexus and capillaries in mice and in astrocytes in humans. Recently, a young patient with progressive neurodegeneration associated with a defective OATP1C1 was identified.

T4 and T3 are also transported by two members of the heterodimeric amino acid transporters LAT1 and LAT2. These transporters are glycoproteins consisting of two subunits, a heavy chain and a light chain. The heavy chains contain a single transmembrane domain, and the light chains contain 12– 14 trans membrane domains. LAT1 is composed of the SLC3A2 (4F2hc or CD98hc) heavy chain and the SLC7A5 light chain, and LAT2 is composed of the same heavy chain and the SLC7A8 light chain.

These transporters are expressed in various tissues and facilitate the bidirectional transport of a variety of aliphatic and aromatic amino acids as well as iodothyronines over the plasma membrane.

Two important thyroid hormone transporters belong to the monocarboxylate transporter (MCT) family. MCT8 and MCT10 have been identified as important thyroid hormone trans porters. Of these, MCT10 also transports the aromatic amino acids Trp, Tyr, and Phe, but so far only iodothyronines have been identified as ligands for MCT8.

Human MCT8 consists of 613 or 539 amino acids, depending on which of the two possible translation start sites is used, and MCT10 has 515 amino acids. They are homologous proteins with about 50% amino acid identity between ‘short’ MCT8 and MCT10 (Figure 1). Like the other MCTs, both MCT8 and MCT10 have 12 transmembrane domains. They have identical gene structures; the MCT8 gene is located on human chromosome Xq13.2, and the MCT10 gene is located on chromosome 6q21- q22. Both consist of six exons and five introns, with a large approximately 100 kb first intron. MCT8 and MCT10 show wide but different tissue distributions.

Fig1. Protein structure of human MCT8 and MCT10.

MCT8 and MCT10 are the most active and specific thyroid hormone transporters known today. MCT8 is importantly expressed in brain, in particular in the endothelial cells of the blood- brain barrier, but is also expressed in astrocytes, neurons, and in the choroid plexus. MCT8 is essential for thyroid hormone uptake in the brain and into neural cells and, thus, for the crucial action of thyroid hormone during brain development. Mutations in MCT8 have been identified as the cause of Allan– Herndon– Dudley syndrome (AHDS). AHDS or MCT8 deficiency occurs in male patients and comprises a severe intellectual and motor disability and a peripheral thyrotoxicosis resulting from highly elevated serum T3 levels.

SLC17A4 transports T3 and T4 to a similar extent as MCT8 and is expressed in the human gastrointestinal tract. Although genetic variation is related to fT4 concentrations, the precise function in physiology is unknown.

Several compounds may affect thyroid hormone uptake through inhibition of transporters (e.g. amiodaron) or changing the expression (e.g. non- thyroidal illness) and as such affect intracellular thyroid hormone bioavailability.

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مواضيع ذات صلة

Role of Thyroid Hormone in Thermogenesis

Metabolism of Thyroid Hormone :Deiodination

Ghrelin, Leptin, and Energy Use

Coordination of Gastroenteropancreatic Hormone Release

Pancreatic, Biliary, and Intestinal Secretions

Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex

Leptin Functions as a Satiety Factor

Glucagon and Glucagon-like Peptides— Biosynthesis and Secretion

Adult Growth Hormone Deficiency

Hypopituitary crisis

Thyroid Replacement in TSH Deficiency

Glucagon’s Structure