Priority Programme: THYROID TRANS ACT
Translation of Thyroid Hormone Actions beyond Classical Concepts

Prof. Dr. Josef Köhrle, Dr. Stefan Mergler

Effects of thyronamines (TAM) and thyroacetic acid (TAC) metabolites on energy metabolism – mitochondrial function, Ca2+-signalling, plasma membrane action

Thyronamines (TAM) are decarboxylated endogenous metabolites of thyroid hormones (TH) which partially antagonize the classical TH. 3T1AM is the prevalent TAM isomer in serum. Its administration reversibly decreases body temperature, RQ, and heart rate, shifting the energy metabolism from glucose to fatty acid oxidation in rodents. This is refelected by hyperglycemia, hyperglucagonemia and hypoinsulinemia. We established a novel 3T1AM immunoassay and detected normal serum levels in thyroidectomized patients on T4 replacement therapy indicating extrathyroidal TAM production. We found efficient TAM deiodination by deiodinase isozymes, but no TAM formation from TH by aromatic amino acid decarboxylase, initially proposed to catalyze this reaction. Now, we plan to test the hypotheses that endogenous TAM are cryogenic agents of the thyromimetic ‘hot’ TH T3 and 3,5-T2, acting antagonistically on TH-target cells. Furthermore, we postulate that TAM affect cellular Ca2+ signalling and that temperature-sensitive receptors such as the transient receptor potential channels (“thermo-TRPs”) of the vanilloid-, melastatin- or ankyrin-subtype family are modulated by TAM in its signalling properties. Therefore, plasma membrane and mitochochondrial TAM effects will be analyzed with/without TH co-stimulation using various cell lines such as HeG2 as well as different eye surface cell models (IOBA  and HCEP) expressing various thermo-TRPs. First data indicated that putative cold receptors (TRPM8) are expressed in human conjunctival epithelial (HCjE) cells using high selective cooling agents (icilin) and the corresponding blocker (BCTC). Furthermore, 3-T1AM activated Ca2+ channels leading to a Ca2+ influx in these cells. Finally, we showed that Ca2+ depletion–replenishment activates TRPs via TAMs in IOBA-NHC and HCEP cells. This protocol was used for functional TRPV6 channel identification and a reliable identification of Ca2+ regulation (cell vitality). These studies will be paralleled by in vitro analyses on TAM formation by type 3 deiodinase and its inactivation by amine oxidases.

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Project Coordinator(s):

Prof. Dr. Josef Köhrle
Charité - Universitätsmedizin Berlin
Institut für Experimentelle Endokrinologie
Augustenburger Platz 1
13353 Berlin
Phone: +49 30 450 524 022
Fax: +49 30 450 524 922

Dr. Stefan Mergler
Charité - Universitätsmedizin Berlin
Klinik für Augenheilkunde - Forschung
AG in vitro Elektrophysiologie/Ionenkanalforschung
Augustenburger Platz 1
13353 Berlin
Phone: +49 30 450 559 648
Fax: +49 30 450 559 948