Differential Modulation of Beta-Adrenergic Receptor Signaling by Trace Amine-Associated Receptor 1 Agonists

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.

Determinants involved in subtype‐specific functions of rat trace amine‐associated receptors 1 and 4

“…However, we observe only minor differences in b-PEA EC50 for chimeras containing TM7 of rat Taar4 (Leu7.39), supporting the finding of Kleinau et al (2011) that this position cannot be assumed crucial for activation by b-PEA. It has been suggested that p-tyramine is probably binding to rat TA1 with its hydroxyl group engaged in hydrogen bond interactions with Ser5.46 (Tan et al, 2009).…”

“…49,Arg3.50,Glu6.30,Trp6.48,Pro6.50,Phe6.52). Furthermore, some ligands are recognized by both Taar and adrenoceptors (Kleinau et al, 2011), supporting a high conservation of the binding pocket.…”

Trace Amines and Their Receptors

“…This has subsequently been verified by numerous laboratories (Mühlhaus et al, 2014;Cöster et al, 2015;Chiellini et al, 2017), with 3IT also shown to act as an agonist at TAAR2 (Babusyte et al, 2013;Cichero and Tonelli, 2017) and as an inverse agonist at TAAR5 (Dinter et al, 2015c). 3IT is promiscuous, however, and also interacts with high affinity at a 2 -adrenoceptors (Regard et al, 2007;Dinter et al, 2015b), b-adrenergic receptors (Meyer and Hesch, 1983;Kleinau et al, 2011;Dinter et al, 2015a), muscarinic acetylcholine receptors (Laurino et al, 2016), transient receptor potential cation channel subfamily M member 8 ion channels (Khajavi et al, 2015;Lucius et al, 2016), various monoamine and organic anion transporters (Snead et al, 2007;Panas et al, 2010), and molecular target(s) within mitochondria, including the F 1 -F 0 ATP synthase (Cumero et al, 2012) and possibly complex III (Venditti et al, 2011). 3IT also tightly binds to the plasma protein apolipoprotein B-100 .…”

Corvitin restores metallothionein and glial fibrillary acidic protein levels in rat brain affected by pituitrin-izadrin

“…Pituitrin is an extract of bovine posterior pituitary hormones, oxytocin, and vasopressin [29] and izadrin is a medication used in the treatment of slow heart rate, heart block, and in rare situations, asthma [30]. Their combined effect causes decreased blood flow, limiting the supply of oxygen and glucose to tissues.…”