Endocrine Abstracts (2011) 26 OC5.5

The effect of MCT8 on the biological activity of T3

A A A van Mullem, R P Peeters & T J Visser

Erasmus MC, Rotterdam, The Netherlands.

Introduction: The biological activity of thyroid hormone (TH) is largely mediated by binding of T3 to nuclear T3 receptors (TRs). Before TH can mediate its effects, it needs to be transported across the plasma membrane. Several TH transporters, such as MCT8, facilitate this transport. Inactivating mutations in MCT8 lead to a severe phenotype of psychomotor retardation. In addition to transport into the cell, MCT8 is also able to transport TH out of the cell. Aim of this study was to investigate if MCT8 does not only increase cellular T3 uptake, but also increases the availability of T3 for its nuclear receptor.

Method: JEG3 cells, transiently transfected with TRβ1 and a construct with a T3 response element (TRE)-dependent luciferase reporter and a control renilla reporter (pdV-L1; gift from Dr W S Simonides, VUMC), were used as a model. μ-crystallin (CRYM), an intracellular TH binding protein, was used to block efflux of TH. In addition to TRβ1 and the reporter construct, cells were transfected with CRYM and/or MCT8. Forty-eight hours after transfection, cells were incubated for 10, 30 or 60 min or 24 h with 0, 0.5 or 1 nM T3.

Results: After 30 min with 1 nM T3, cells transfected with TRβ1, reporter and CRYM had a significantly higher luciferase/renilla ratio after co-transfection with MCT8 than without MCT8 (0.60±0.07 vs 0.20±0.01, P<0.001). Similar differences were seen after the other incubation times, and with 0.5 nM T3. However, in cells transfected with TRβ1 and reporter, but without CRYM, co-transfection with MCT8 had no effect on the luciferase/renilla ratio at any of the incubation times or ligand concentrations.

Conclusion: MCT8 contributes to both influx and efflux of TH. Our data suggest that in cells with high intracellular binding capacity, MCT8 increases the availability of T3 for its receptor, and has a positive effect on T3-mediated gene transcription.

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