title: Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3.
abstract: Transport of thyroid hormone (TH) across the plasma membrane is necessary for the genomic action of T3 mediated by its nuclear T3 receptor. MCT8 and MCT10 have been identified as important TH transporters. Mutations in MCT8 result in severe psychomotor retardation. In addition to TH transport into the cell, MCT8 and MCT10 also facilitate TH efflux from cells. Therefore, the aim of this study was to examine if MCT8 and MCT10 increase the availability of T3 for its nuclear receptor rather than generate a rapid equilibrium between cellular and serum T3. T3 action was investigated in JEG3 cells co-transfected with TRβ1 and a T3 response element-driven luciferase construct, and T3 metabolism was analyzed in cells transfected with type 3 deiodinase (D3). In addition, cells were transfected with MCT8 or MCT10 and/or the cytoplasmic T3-binding protein mu-crystallin (CRYM). Luciferase signal was markedly stimulated by incubating cells for 24 h with 1 nM T3, but this response was not augmented by MCT8 or MCT10 expression. Limiting the time of T3 exposure to 1-6 h and co-transfection with CRYM allowed for a modest increase in luciferase response to T3. In contrast, T3 metabolism by D3 was potently stimulated by MCT8 or MCT10 expression, but it was not affected by expression of CRYM. These results suggest that MCT8 and MCT10 by virtue of their bidirectional T3 transport have less effect on steady-state nuclear T3 levels than on T3 levels at the cell periphery where D3 is located. CRYM alters the dynamics of cellular TH transport but its exact function in the cellular distribution of TH remains to be determined.
authors: Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Alies A
authors: AA
authors: van Mullem
authors: Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Anja L M
authors: ALM
authors: van Gucht
authors: Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: W Edward
authors: WE
authors: Visser
authors: Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Marcel E
authors: ME
authors: Meima
authors: Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Robin P
authors: RP
authors: Peeters
authors: Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: t.j.visser@erasmusmc.nl.
authors: Theo J
authors: TJ
authors: Visser
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D027981:Symporters; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology*; D000090803:mu-Crystallins
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C000716469:CRYM protein, human; D027501:Monocarboxylic Acid Transporters; C498964:SLC16A10 protein, human; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine; D000090803:mu-Crystallins
keywords: Deiodinase; Nuclear receptor; Thyroid hormone; Transporter