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.