Academic Journal
In Vitro Characterization of Human, Mouse, and Zebrafish MCT8 Orthologues.
| العنوان: | In Vitro Characterization of Human, Mouse, and Zebrafish MCT8 Orthologues. |
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| المؤلفون: | Groeneweg, S., Kersseboom, S., Berge, A. ten, Dolcetta-Capuzzo, A., Geest, F.S. van, Heerebeek, R.E.A. van, Arjona, F.J., Meima, M.E., Peeters, R.P., Visser, W.E., Visser, T.J. |
| المصدر: | Thyroid, 29, 10, pp. 1499-1510 |
| سنة النشر: | 2019 |
| المجموعة: | Radboud University: DSpace |
| مصطلحات موضوعية: | Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences |
| الوصف: | Contains fulltext : 215814.pdf (Publisher’s version ) (Closed access) ; Background: Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) cause MCT8 deficiency, characterized by severe intellectual and motor disability and abnormal serum thyroid function tests. Various Mct8 knock-out mouse models as well as mct8 knock-out and knockdown zebrafish models are used as a disease model for MCT8 deficiency. Although important for model eligibility, little is known about the functional characteristics of the MCT8 orthologues in these species. Therefore, we here compared the functional characteristics of mouse (mm) MCT8 and zebrafish (dr) Mct8 to human (hs) MCT8. Methods: We performed extensive transport studies in COS-1 and JEG-3 cells transiently transfected with hsMCT8, drMct8, and mmMCT8. Protein expression levels and subcellular localization were assessed by immunoblotting, surface biotinylation, and immunocytochemistry. Sequence alignment and structural modeling were used to interpret functional differences between the orthologues. Results: hsMCT8, drMct8, and mmMCT8 all facilitated the uptake and efflux of 3,3'-diiodothyronine (3,3'-T2), rT3, triiodothyronine (T3), and thyroxine (T4), although the initial uptake rates of drMct8 were 1.5-4.0-fold higher than for hsMCT8 and mmMCT8. drMct8 exhibited 3-50-fold lower apparent IC50 values than hsMCT8 and mmMCT8 for all tested substrates, and substrate preference of drMct8 (3,3'-T2, T3 > T4 > rT3) differed from hsMCT8 and mmMCT8 (T3 > T4 > rT3, 3,3'-T2). Compared with hsMCT8 and mmMCT8, cis-inhibition studies showed that T3 uptake by drMct8 was inhibited at a lower concentration and by a broader spectrum of TH metabolites. Total and cell surface expression levels of drMct8 and hsMCT8 were equal and both significantly exceeded those of mmMCT8. Structural modeling located most non-conserved residues outside the substrate pore, except for H192 in hsMCT8, which is replaced by a glutamine in drMct8. However, a H192Q substituent of ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://hdl.handle.net/2066/215814 |
| DOI: | 10.1089/thy.2019.0009 |
| الاتاحة: | https://hdl.handle.net/2066/215814 https://doi.org/10.1089/thy.2019.0009 |
| رقم الانضمام: | edsbas.B2187EA0 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1089/thy.2019.0009 |
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