Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile

The thyroid hormone derivative 3-iodothyronamine (3-T(1)AM) exerts metabolic effects in vivo that contradict known effects of thyroid hormones. 3-T(1)AM acts as a trace amine-associated receptor 1 (TAAR1) agonist and activates G(s) signaling in vitro. Interestingly, 3-T(1)AM-meditated in vivo effects persist in Taar1 knockout-mice indicating that further targets of 3-T(1)AM might exist. Here, we investigated another member of the TAAR family, the only scarcely studied mouse and human trace-amine-associated receptor 8 (Taar8b, TAAR8). By RT-qPCR and locked-nucleic-acid (LNA) in situ hybridization, Taar8b expression in different mouse tissues was analyzed. Functionally, we characterized TAAR8 and Taar8b with regard to cell surface expression and signaling via different G-protein-mediated pathways. Cell surface expression was verified by ELISA, and cAMP accumulation was quantified by AlphaScreen for detection of G(s) and/or G(i/o) signaling. Activation of G-proteins G(q/11) and G(12/13) was analyzed by reporter gene assays. Expression analyses revealed at most marginal Taar8b expression and no gender differences for almost all analyzed tissues. In heart, LNA-in situ hybridization demonstrated the absence of Taar8b expression. We could not identify 3-T(1)AM as a ligand for TAAR8 and Taar8b, but both receptors were characterized by a basal G(i/o) signaling activity, a so far unknown signaling pathway for TAARs.