Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5

Objective Application of 3-iodothyronamine (3-T 1 AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T 1 AM. However, 3-T 1 AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T 1 AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct G s -, G i/o -, G 12/13 -, G q/11 - and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T 1 AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the G q/11 pathway but show differences in the basal activity in G s and MAP kinase signaling. In contrast to mTaar5, 3-T 1 AM application at hTAAR5 resulted in significant reduction in basal IP 3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T 1 AM, exhibiting inhibitory effects on IP 3 formation and MAP kinase signaling pathways, but does not mediate G s signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T 1 AM-mediated effects may differ between rodents and humans.