Transport Across the Cell Membrane

The deiodinases involved in T4 to T3 conversion and T4 and T3 degradation as well as the T3 receptors are located intracellularly. Therefore, both action and metabolism of thyroid hormones are intracellular events requiring transport of iodothyronines across the cell membrane. For a long time it was believed that TH diffused passively over the cell membrane, but recent years of research has made it increasingly clear that cellular transmembrane transport of TH is mediated by transporters, that these transporters determine the availability of iodothyronines to the intracellular sites for metabolism and action [19], and that the TH transport is energy dependent [20] (fig. 1). Recently, specific transporters (organic anion transporters and amino acid transporters) known to facilitate cellular thyroid hormone uptake have been identified [20-22]. Hennemann and Visser [22] have defined requirements for (patho)physiological significance of thyroid hormone plasma membrane transport in the terms that it should be specific, without significant diffusion, plasma membrane transport subject to regulation, transport rate limiting on subsequent metabolism, and changes in transport should be appropriate from the (patho)physiological point of view.

Organic Anion Transporters

These mediate uptake of iodothyronines and their sulphonated derivatives and they are members of the Na+/taurocholate cotransporting polypeptide (NTCP) and the Na+-independent organic anion transporting polypeptide (OATP) families [23, 24]. NTCP is only expressed on hepatocytes and is the major transporter of conjugated bile acids in the liver. The OATPs are a large family responsible for transmembrane transport of a number of compounds including TH. The most interesting OATP superfamily members in terms of TH transport are OATP1C1 and OATP14. The former has been demonstrated to be widely expressed both in human brain and the Leydig cells of testis [25]. In the brain they seem to participate in maintaining the T3 concentration along with parallel changes in D2 expression. It has been demonstrated that the thyroid state modulates OATP1C1, and by doing so counteracts the effects of alterations in circulating T4 levels on brain T4 uptake [26, 27]. In humans, OATP1C1 is also expressed in the testis where also D2 expression has been demonstrated [28]. This combination supports a role of TH in development, growth and differentiation of Leydig cells. In particular T3 is very important for testosterone biosynthesis and may therefore have an important role in male puberty. Other OATPs have been demonstrated in a number of other tissues and may exert a variety of effects, but this is not well clarified, and they are possibly less tissue-specific considering the widespread expression [21]. Some characteristics of the transporters are shown in table 2 [29-39].

Amino Acid Transporters

Iodothyronines are a particular class of amino acids built from two tyrosine residues implying transport by specific amino acid transporters, in particular the L and T type amino acid transporters, which therefore are involved in TH uptake into several tissues [40-44]. Among those are members of the het-erodimeric amino acid transporter (HAT) family. Their exact role is not clear, but it has been demonstrated that overexpression of the heterodimer L-type transporter in cells resulted in increased intracellular T3 availability and a consequent augmentation of T3 action [45]. Evidence has also been presented to suggest a role of members from the HAT family in supplying the placenta and developing fetus with thyroid hormone [46].

The monocarboxylate transporter (MCT) family comprise to date 14 identified members in various tissues from different species [21]. MCTs are dispersed over autosomal chromosomes, except MCT8, which is X-linked [47]

Table 2. Characteristics of thyroid hormone transporters

Gene

Protein

Species

Accession code

Chromosome

Tissue distribution

Iodothyroine transport

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