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

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 bind-ing 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 concentra-tion, 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 sup-ply 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 di-rectly 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 exchan-ge 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 ex-pressed 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 ute-rus, 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 homo-logous 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 io-dothyronines across the cell membrane. This does not take place by passive diffu-sion but requires the involvement of specific transporters (2). A number of multi--specific transporters have been identified which are also capable of transporting TH.