Trace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled 
receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and 
vascular functions and they are potentially linked with neurological disorders 
like schizophrenia and Parkinson's disease. Subtype TAAR1, the best 
characterized TAAR so far, is promiscuous for a wide set of ligands and is 
activated by trace amines tyramine (TYR), phenylethylamine (PEA), octopamine 
(OA), but also by thyronamines, dopamine, and psycho-active drugs. 
Unfortunately, effects of trace amines on signaling of the two homologous 
β-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in 
detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their 
effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace 
amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is 
a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular 
reasons for TAAR1 ligand promiscuity and for observed differences in signaling 
effects on particular aminergic receptors we compared TAAR, tyramine (TAR) 
octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We 
found especially for TAAR1 that the remarkable ligand promiscuity is likely 
based on high amino acid similarity in the ligand-binding region compared with 
further aminergic receptors. On the other hand few TAAR specific properties in 
the ligand-binding site might determine differences in ligand-induced effects 
compared to ADRB1/2. Taken together, this study points to molecular details of 
TAAR1-ligand promiscuity and identified specific trace amines as allosteric or 
orthosteric ligands of particular β-adrenergic receptor subtypes.