Searching for transport proteins for TRIAC acting as T3 /TH substitutes (J. Protze, G. Krause)

The Thyroid hormone (TH) 3,3`,5-triiodo-L-thyronine (T3) is essential for many physiological processes such as cell metabolisms and development, especially of the human central nervous system. It plays an important role in differentiation of neurons, formation of synaptic contacts and myelination. Before THs are reaching their target–the thyroid hormone receptor (TR) located in the nucleus of the target cells– they have to cross cell borders between several cells via transporter proteins the thyroid hormone transmembrane transporters (THTT).

It was recently shown that the TH analogue TRIAC (3,3',5, -triiodothyroacetic acid) can bypass disturbed (deficient) THTT, such as the monocarboxylate transporter 8 (MCT8) and can also activate the TR. This makes TRIAC highly interesting for pharmacological intervention in diseases such as Allan-Herndon-Dudley Syndrome (AHDS), in which there are mutational defects of the MCT8. Elucidating the molecular context of how TRIAC bypasses MCT8 to overcome membrane barriers is of great importance for the further pharmacological development of therapeutic agents for AHDS.

In our project funded by the Deutsche Forschungsgemeinschaft we are searching for the hitherto unknown membrane transport protein but also intracellular transport protein(s) for TRIAC using RNAi screening technology of the Screening Unit of the FMP, (cooperation with J v. Kries, FMP). In preparation for the whole human genome siRNA-screen we developed a highly sensitive TR activation assay with which concentrations of TH and derivatives can be measured in the physiological (pmol/l) range. To this end, we are cooperating also with the research groups T. Jentsch MDC/FMP Berlin; L. Schomburg, H. Biebermann, F. Köhrle Charité-Universitätsmedizin Berlin, R. Lauster, Technical University Berlin, and T. Müller Helmholtz Institute for Diabetes and Obesity München.



Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
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