Thyroid hormone transporters in the brain

Abstract

Thyroid hormone plays an essential role in proper mammalian development of the central nervous system and peripheral tissues. Lack of sufficient thyroid hormone results in abnormal development of virtually all organ systems, a syndrome termed cretinism. In particular, hypothyroidism in the neonatal period causes serious damage to neural cells and leads to mental retardation. Although thyroxine is the major product secreted by the thyroid follicular cells, the action of thyroid hormone is mediated mainly through the deiodination of T(4) to the biologically active form 3,3', 5-triiodo-L-thyronine, followed by the binding of T(3) to a specific nuclear receptor. Before reaching the intracellular targets, thyroid hormone must cross the plasma membrane. Because of the lipophilic nature of thyroid hormone, it was thought that they traversed the plasma membrane by simple diffusion. However, in the past decade, a membrane transport system for thyroid hormone has been postulated to exist in various tissues. Several classes of transporters, organic anion transporter polypeptide (oatp) family, Na(+)/Taurocholate cotransporting polypeptide (ntcp) and amino acid transporters have been reported to transport thyroid hormones. Monocarboxylate transporter8 (MCT8) has recently been identified as an active and specific thyroid hormone transporter. Mutations in MCT8 are associated with severe X-linked psycomotor retardation and strongly elevated serum T3 levels in young male patients. Several other molecules should be contributed to exert the role of thyroid hormone in the central nervous system.

Thyroid hormone transporters and deiodinases in the developing human hypothalamus

“…Wirth et al (41) suggest that the L-type amino acid transporter LAT2 might compensate in the mouse but not in the human brain for the lack of MCT8 as only a low LAT2 expression was found in developing neurons in the human brain. Also, the rat brain expresses the TH transporter variants OATP1A4 and OATP1A5, but to our knowledge, both transporters have no ortholog in the human brain (39).…”

“…Defects in the human MCT8 gene lead to severe X-linked psychomotor retardation in combination with elevated serum T 3 concentrations, also known as AHDS (38). The striking differences in the neurological phenotype between Mct8-null mice and MCT8 patients have been proposed to result from interspecies differences in the expression (or subset) of TH transporters in the central nervous system (39,40). The clear expression of MCT10 and OATP1C1 already in the second trimester of pregnancy suggests that MCT10 and OATP1C1 cannot compensate for the MCT8 deletion in AHDS.…”

Maternal thyroid dysfunction and neonatal cardiac disorders

“…The actions of THs are facilitated genomically by thyroid receptors (TRs, α and β) and non-genomically at the plasma membrane, in the cytoplasm and in cellular organelles [4,[49][50][51][52][53][54][55], by stimulation of Na+, K+, Ca2+ and glucose transport, activation of protein kinase C (PKC), protein kinase A (PKA) and mitogen activated and protein kinase (ERK/MAPK) [4]. In addition, the transport of T4 and T3 in and out of cells is controlled by several classes of transmembrane TH-transporters (THTs) [56], including members of the organic anion transporter family (OATP), L-type amino acid transporters (LATs), Na+/Taurocholate cotransporting polypeptide (NTCP), and monocarboxylate transporters (MCTs) [4,49,57,58]. Adding additional complexity, the metabolism of T4 and T3 is regulated by 3 selenoenzyme iodothyronine deiodinases (Ds: D1, D2 and D3) [59][60][61].…”

Hormones and Cerebellar Development

“…Because of their chemical nature, these may be able to cross blood-brain barrier more easily than peptide hormones, although existence of specific transporters has been proposed (Suzuki and Abe 2008). Receptors for such lipophilic hormones are mainly located in the cell nucleus (nuclear receptor, NR), and represent the largest family of ligand-regulated transcription factors (Mangelsdorf et al 1995).…”