Specific thyroid hormone transporters
Both action and metabolism of thyroid hormone are intracellular events which require the transport of iodothyronines across the plasma membrane. This does not occur by simple diffusion but is facilitated by transport proteins. During the last few years thyroid hormone transporters have been characterized at the molecular level. These include the Na+-taurocholate cotransporting polypeptide (NTCP), different members of the Na+-independent organic anion transporting polypeptide (OATP) family, the heterodimeric L-type amino acid transporters LAT1, LAT2, and the monocarboxylate transporter 8 (MCT8). Most of these transporters accept a variety of ligands, but OATP1C1 and MCT8 show high specificity towards iodothyronines. OATP1C1 is almost exclusively expressed in brain capillaries, and appears crucial for the transport of the prohormone T4 across the blood-brain barrier. MCT8 is also expressed among other tissues - in the brain, in particular in neurons. MCT8 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 type 2 deiodinase in neighbouring astrocytes. The neurons express type 3 deiodinase which inactivates T3. The MCT8 gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe X-linked psychomotor retardation and high serum T3 levels. In over 20 families, where affected males present this syndrome, different mutations have been identified in MCT8. 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.