Exp Clin Endocrinol Diabetes 2014; 122 - OP7_38
DOI: 10.1055/s-0034-1372013

Aspects of 3-iodothyronamine (3T1AM) induced signaling by human and mouse trace amine-associated receptor 5 (TAAR5)

J Mühlhaus 1, J Dinter 1, CL Piechowski 1, A Müller 1, D Nürnberg 1, A Grüters 1, J Köhrle 2, CX Yi 3, M Tschöp 3, H Krude 1, G Kleinau 1, H Biebermann 1
  • 1Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Institute for Experimental Pediatric Endocrinology, Berlin, Germany
  • 2Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Institute for Experimental Endocrinology, Berlin, Germany
  • 3Helmholtz Zentrum München, German Research Center for Environmental Health, Institute for Diabetes and Obesity, Garching, Germany

The thyroid hormone derivative 3-iodothyronamine (3T1AM) is an agonist for trace amine-associated receptor 1 (TAAR1). Application of 3T1AM in rodents results in a variety of effects, including decreased body temperature. Taar1-/- mice still show these effects, excluding Taar1 as primary mediator of 3T1AM induced action in vivo. Because of its role as potential treatment option for stroke patients, possible targets and effects of 3T1AM in humans are of medical interest.

Here we investigated the human (hTAAR5) and mouse Taar5 (mTaar5) as potential target to explain 3T1AM effects in Taar1-/- mice.

In situ hybridization for mTaar1 and mTaar5 revealed overlapping expression profiles in the amygdala and VMH. Next, we investigated several signaling pathways of mTaar5 and hTAAR5.

We confirmed previously reported data that the volatile amine dimethylethylamine is an agonist for Gs activation by mTaar5, however, not for hTAAR5. Further investigations revealed a basal tone of ERK and Gq activation for hTAAR5 and mTaar5 and additional basal Gs activity for mTaar5 mediating cAMP accumulation.

In response to 3T1AM, no signaling via Gs, Gq, Gi, G12/13 and ERK was observed for hTAAR5 and mTaar5, while 3T1AM acted as inverse agonist on hTAAR5 by decreasing the basal tone of IP3 accumulation and ERK.

To elucidate the particular determinants involved in signaling differences between hTAAR5 and mTaar5 we created chimeric receptors, aiming to transfer murine signaling properties to hTAAR5. We identified 6 amino acids in the ligand binding and G protein-coupling region to be involved.

Our data demonstrated that caution is needed when transferring signaling properties of mTaar5 to the human situation. While observed pharmacological effects of 3T1AM on Taar1-/- mice are likely not related to mTaar5, according to our in vitro data, hTAAR5 functions as a target for 3T1AM and exhibits inhibitory 3T1AM effects on Gq and ERK signaling.

Supported by DFG-SPP1629 ThyroidTransAct