Effective Cellular Uptake and Efflux of Thyroid Hormone by Human Monocarboxylate Transporter 10

Abstract

Cellular entry of thyroid hormone is mediated by plasma membrane transporters, among others a T-type (aromatic) amino acid transporter. Monocarboxylate transporter 10 (MCT10) has been reported to transport aromatic amino acids but not iodothyronines. Within the MCT family, MCT10 is most homologous to MCT8, which is a very important iodothyronine transporter but does not transport amino acids. In view of this paradox, we decided to reinvestigate the possible transport of thyroid hormone by human (h) MCT10 in comparison with hMCT8. Transfection of COS1 cells with hMCT10 cDNA resulted in 1) the production of an approximately 55 kDa protein located to the plasma membrane as shown by immunoblotting and confocal microscopy, 2) a strong increase in the affinity labeling of intracellular type I deiodinase by N-bromoacetyl-[(125)I]T(3), 3) a marked stimulation of cellular T(4) and, particularly, T(3) uptake, 4) a significant inhibition of T(3) uptake by phenylalanine, tyrosine, and tryptophan of 12.5%, 22.2%, and 51.4%, respectively, and 5) a marked increase in the intracellular deiodination of T(4) and T(3) by different deiodinases. Cotransfection studies using the cytosolic thyroid hormone-binding protein micro-crystallin (CRYM) indicated that hMCT10 facilitates both cellular uptake and efflux of T(4) and T(3). In the absence of CRYM, hMCT10 and hMCT8 increased T(3) uptake after 5 min incubation up to 4.0- and 1.9-fold, and in the presence of CRYM up to 6.9- and 5.8-fold, respectively. hMCT10 was less active toward T(4) than hMCT8. These findings establish that hMCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate iodothyronine uptake as well as efflux.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…With the exception of OATP1C1 (T 4 and 3,3¢,5¢-triiodothyronine [rT 3 ] transport only), most thyroid hormone transporters transport both T 4 and T 3 . It is important to realize that members of the MCT family, such as MCT8 and MCT10, facilitate not only the cellular uptake, but also the efflux of iodothyronines (109). The physiological role of the transporters is not only dependent on their relative affinities for the thyroid hormones but also depend upon tissue-and cell-specific expression patterns.…”

“…Accumulation of transported thyroid hormones in the cell is necessary for assessing transport activity and can present a problem for some bidirectional transporters because the substrate may rapidly efflux thyroid hormones from the cell. Co-transfection with intracellular thyroid hormone binding proteins such as mucrystallin provides a method for ensuring accumulation of transported hormone (109,115,116). One caveat, however, is that use of such methods precludes subsequent kinetic studies because hormone transport will likely not ever reach steadystate.…”

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

“…These genes encode proteins of several functional classes including tumorigenesis (EPB41L3, KIAA1210, SALL3), cell adhesion and migration (RIAM, LAMB1), or intracellular transport (SLC16A10, PACSIN3, DNM1; refs. [25][26][27][28][29][30][31][32].…”

Thyroid hormone action during brain development: More questions than answers

“…Putative candidates include the member of the L-type amino acid transporter family of which particularly h4F2hc/hLAT1 and h4F2hc/mLAT2 transport T4 and T3 when overexpressed in Xenopus oocytes . Moreover, as another interesting candidate the contribution of the monocarboxylate transporter MCT10 to thyroid hormone transport in the CNS needs to be evaluated particularly because MCT10 does not only very efficiently transport thyroid hormones (Friesema et al, 2008) but is also highly expressed in murine oligodendrocytes (unpubl. observations).…”