Abstract
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.
Highlights
The group of trace amine-associated receptors (TAAR) [1] belongs to the rhodopsin-like family of G protein-coupled receptors (GPCRs) and is of importance for several physiological aspects such as proper cardiac and vascular functions
HTAAR1 exhibits a high level of basal constitutive signaling activity (73614 nM cyclic adenosine-monophosphate (cAMP)) compared to mock transfected cells
That the ligand-binding region of TAAR1 is characterized by high similarity to other aminergic GPCR like ADRB1, DRD3 or tyramine receptors (TAR)/octopamine receptors (OAR)
Summary
The group of trace amine-associated receptors (TAAR) [1] belongs to the rhodopsin-like family of G protein-coupled receptors (GPCRs) and is of importance for several physiological aspects such as proper cardiac and vascular functions (reviews [2,3,4,5]). TAAR1 is activated by trace amines [6] such as tyramine (TYR), bphenylethylamine (PEA) or octopamine (OA) [17,19] and signals via the Gs protein/adenylyl cyclase system. Ligands of the dopamine-, serotonine-, histamine-, or adrenergic receptors are able to induce TAAR1 mediated signaling [17,19,31,32]. TAAR1 responds to psycho-active drugs [19,37] This points, altogether, to an enormous TAAR1 ligand-binding promiscuity that might reflect the evolutionary link between TAAR and homologous vertebrate aminergic receptors [2,17,18,38,39,40] or invertebrate tyramine receptors (TAR) and octopamine receptors (OAR)
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