Importance of transporters for cellular entry of thyroid hormone
Theo J Visser
Action and metabolism of thyroid hormone are intracellular events which require the transport of iodothyronines across the plasma membrane through transporters. In recent years, several transporters have been identified which are capable of transporting thyroid hormone. They are members of different transporter families, including organic anion transporting polypeptides (OATPs) family, heterodimeric amino acid transporters (HATs), and monocarboxylate transporters (MCTs). In particular, OATP1C1, MCT8 and MCT10 are interesting as they show a high activity and specifity towards iodothyronines.
OATP1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the transport of the prohormone T4 across the blood-brain barrier. MCT8 is expressed in different tissues, including the brain where it is located predominantly in neurons. It appears especially important for the uptake of the active hormone T3 into these cells which is essential for optimal brain development. This T3 is produced from T4 by the type II deiodinase (D2) expressed in neighbouring astrocytes. In addition to the nuclear T3 receptors, many neurons als express the type III deiodinase (D3) which catalyzes the inactivation of T3.
The MCT8 gene is located on the X chromosome, and mutations in MCT8 have recently been associated with a syndrome combining severe X-linked psychomotor retardation and high serum T3 levels. The mechanism of this disease involves a defect in the neuronal entry of T3, and thus in the action and metabolism of T3 in these cells, leading to an impaired neurological development as well as a decrease in T3 clearance. This syndrome therefore represents a novel type of thyroid hormone resistance caused by a defect in the entry of the active hormone T3 in its target cells.